Glycinamide derivatives as raf-kinase inhbitors

ABSTRACT

The present invention relates to glycinamide derivatives of formula I, 
       A-D-B  (I), 
     wherein A, D, and B are as herein defined, as well as the use of the compounds of formula I as inhibitors of raf-kinase, the use of the compounds of formula I for the manufacture of a pharmaceutical composition, and a method of treatment comprising administering said pharmaceutical composition to a patient.

The present invention relates to glycine amide derivatives, glycine amide derivatives as medicaments, glycine amide derivatives as inhibitors of raf-kinase, the use of glycine amide derivatives for the manufacture of a pharmaceutical, a method for producing a pharmaceutical composition containing said glycine amide derivatives, the pharmaceutical composition obtainable by said method and a method of treatment, comprising administering said pharmaceutical composition.

Protein phosphorylation is a fundamental process for the regulation of cellular functions. The coordinated action of both protein kinases and phosphatases controls the levels of phosphorylation and, hence, the activity of specific target proteins. One of the predominant roles of protein phosphorylation is in signal transduction, where extracellular signals are amplified and propagated by a cascade of protein phosphorylation and dephosphorylation events, e.g. in the p21^(ras)/raf pathway.

The p21^(ras) gene was discovered as an oncogene of the Harvey (rash) and Kirsten (rasK) rat sarcoma viruses. In humans, characteristic mutations in the cellular ras gene (c-ras) have been associated with many different types of cancers. These mutant alleles, which render Ras constitutively active, have been shown to transform cells, such as the murine cell line NIH 3T3, in culture.

The p21^(ras) oncogene is a major contributor to the development and progression of human solid cancers and is mutated in 30% of all human cancers (Bolton et al. (1994) Ann. Rep. Med. Chem., 29, 165-74; Bos. (1989) Cancer Res., 49, 4682-9). In its normal, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost ltittissues (Avruch et al. (1994) Trends Biochem. Sci., 19, 279-83).

Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-bound resting form is strictly controlled by ras endogenous GTPase activity and other regulatory proteins. The ras gene product binds to guanine triphosphate (GTP) and guanine diphosphate (GDP) and hydrolyzes GTP to GDP. It is the GTP-bound state of Ras that is active. In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants (Magnuson et al. (1994) Semin. Cancer Biol., 5, 247-53). The ras proto-oncogene requires a functionally intact c-rat1 proto-oncogene in order to transduce growth and differentiation signals initiated by receptor and non-receptor tyrosine kinases in higher eukaryotes.

Activated Ras is necessary for the activation of the c-raf1 proto-oncogene, but the biochemical steps through which Ras activates the Rat-1 protein (Ser/Thr) kinase are now well characterized. It has been shown that inhibiting the effect of active ras by inhibiting the rat kinase signaling pathway by administration of deactivating antibodies to rat kinase or by co-expression of dominant negative rat kinase or dominant negative MEK (MAPKK), the substrate of rat kinase, leads to the reversion of transformed cells to the normal growth phenotype see. Daum et al. (1994) Trends Biochem. Sci., 19, 474-80; Fridman et al. (1994) J. Biol. Chem., 269, 30105-8. Kolch et al. (1991) Nature, 349, 426-28) and for review Weinstein-Oppenheimer et al. Pharm. & Therap. (2000), 88, 229-279.

Similarly, inhibition of rat kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2, 668-75).

Raf serine- and threonine-specific protein kinases are cytosolic enzymes that stimulate cell growth in a variety of cell systems (Rapp, U. R., et al. (1988) in The oncogene handbook; T. Curran, E. P. Reddy, and A. Skalka (ed.) Elsevier Science Publishers; The Netherlands, pp. 213-258; Rapp, U. R., et al. (1988) Cold Spring Harbor Sym. Quant. Biol. 53:173-184; Rapp, U. R., et al. (1990) Inv Curr. Top. Microbiol. Amunol. Potter and Melchers (eds), Berlin, Springer-Verlag 166:129-139).

Three isozymes have been characterized:

c-Rat (Raf-1) (Bonner, T. I., et al. (1986) Nucleic Acids Res. 14:1009-1015). A-Raf (Beck, T. W., et al. (1987) Nucleic Acids Res. 15:595-609), and B-Raf (Qkawa, S., et al. (1998) Mol. Cell. Biol. 8:2651-2654; Sithanandam, G. et al. (1990) Oncogene: 1775). These enzymes differ in their expression in various tissues. Raf-1 is expressed in all organs and in all cell lines that have been examined, and A- and B-Raf are expressed in urogenital and brain tissues, respectively (Storm, S. M. (1990) Oncogene 5:345-351).

Rat genes are proto-oncogenes: they can initiate malignant transformation of cells when expressed in specifically altered forms. Genetic changes that lead to oncogenic activation generate a constitutively active protein kinase by removal or interference with an N-terminal negative regulatory domain of the protein (Heidecker, G., et al. (1990) Mol. Cell. Biol. 10:2503-2512; Rapp, U. R., et al. (1987) in Oncogenes and cancer S. A. Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshima, and P. K. Vogt (ed). Japan Scientific Press, Tokyo). Microinjection into NIH 3T3 cells of oncogenically activated but not wild-type versions of the Raf-protein prepared with Escherichia coli expression vectors results in morphological transformation and stimulates DNA synthesis (Rapp, U. R., et al. (1987) in Oncogenes and cancer; S. A. Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshima, and P. K. Vogt (ed.) Japan Scientific Press, Tokyo; Smith, M. R., et al (1990) Mol. Cell. Biol. 10:3828-3833). Activating mutants of B-Rat have been identified in a wide range of human cancers e.g. colon, ovarien, melanomas and sarcomas (Davies, H., et al. (2002), Nature 417 949-945. Published online Jun. 9, 2002, 10.1038/nature00766). The preponderant mutation is a single phosphomimetic substitution in the kinase activation domain (V599E), leading to constitutive kinase activity and transformation of NIH3T3 cells.

Thus, activated Raf-1 is an intracellular activator of cell growth. Raf-1 protein serine kinase in a candidate downstream effector of mitogen signal transduction, since Raf oncogenes overcome growth arrest resulting from a block of cellular ras activity due either to a cellular mutaton (ras revertant cells) or microinjection of anti-ras antibodies (Rapp, U. R., et al. (1988) in The Oncogene Handbook, T. Curran, E. P. Reddy, and A. Skalka (ed.), Elsevier Science Publishers; The Netherlands, pp. 213-253; Smith, M. R., et al. (1986) Nature (London) 320:540-543).

c-Raf function is required for transformation by a variety of membrane-bound oncogenes and for growth stimulation by mitogens contained in serums (Smith, M. R., et al. (1986) Nature (London) 320:540-543). Raf-1 protein serine kinase activity is regulated by mitogens via phosphorylation (Morrison, D. K., et al. (1989) Cell 58:648-657), which also effects sub cellular distribution (Olah, Z., et al. (1991) Exp. Brain Res, 84:403; Rapp, U. R., et al. (1988) Cold Spring Harbor Sym. Quant. Biol. 53:173-184. Rat-1 activating growth factors include platelet-derived growth factor (PDGF) (Morrison, D. K., et al. (1988) Proc. Natl. Acad. Sci. USA 85:8855-8859), colony-stimulating factor (Baccarini, M., et al. (1990) EMBO J. 9:3649-3657), insulin (Blackshear, P. J., et al. (1990) J. Biol. Chem. 265:12115-12118), epidermal growth factor (EGF) (Morrison, R. K., et al. (1988) Proc. Natl. Acad. Sci. USA 85:8855-8859), interleukin 2 (Turner, B. C., et al (1991) Proc. Natl. Acad. Sci. USA 88:1227), and interleukin 3 and granulocytemacrophage colony-stimulating factor (Carroll, M. P., et al (1990) J. Biol. Chem. 265:19812-19817).

Upon mitogen treatment of cells, the transiently activated Raf-1 protein serine kinase translocates to the perinuclear area and the nucleus (Olah, Z., et al. (1991) Exp. Brain Res. 84:403; Rapp, U. R., et al. (1988) Cold Spring Habor Sym, Quant. Biol. 53:173-184). Cells containing activated Raf are altered in their pattern of gene expression (Heidecker, G., et al. (1989) in Genes and signal transduction in multistage carcinogenesis, N. Colburn (ed.), Marcel Dekker, Inc., New York, pp. 339-374), and Rat oncogenes activate transcription from Ap-I/PEA3-dependent promoters In transient transfection assays (Jamal, S., et al (1990) Science 344:463-466; Kaibuchi, K., et al (1989) J. Biol. Chem. 264:20855-20858; Wasylyk, C., et al. (1989) Mol. Cell. Biol. 9:2247-2250).

There are at least two independent pathways for Raf-1 activation by extracellular mitogens: one involving protein kinase C (KC) and a second initiated by protein tyrosine kinases (Blackshear, P. J., et al. (1990) J. Biol. Chem. 265:12131-12134; Kovacina, K. S., et al (1990) J. Biol. Chem. 265:12115-12118; Morrison, D. K., et al. (1988) Proc. Natl. Acad. Sci. USA 85:8856-8859; Siegel, J. N., et al (1990) J. Biol. Chem. 265:18472-18480; Turner, B. C., et al (1991) Proc. Natl. Acad. Sol. USA 88:1227). In either case, activation involves Raf-1 protein phosphorylation. Raf-1 phosphorylation may be a consequence of a kinase cascade amplified by autophosphorylation or may be caused entirely by autophosphorylation initiated by binding of a putative activating ligand to the Raf-1 regulatory domain, analogous to PKC activation by diacylglycerol (Nishizuka, Y. (1986) Science 233:305-312).

The process of angiogenesis is the development of new blood vessels, generally capillaries, from pre-existing vasculature. Angiogenesis is defined as involving (i) activation of endothelial cells; (ii) increased vascular permeability; (iii) subsequent dissolution of the basement membrane and extravisation of plasma components leading to formation of a provisional fibrin gel extracellular matrix; (iv) proliferation and mobilization of endothelial cells; (v) reorganization of mobilized endothelial cells to form functional capillaries; (vi) capillary loop formation; and (vii) deposition of basement membrane and recruitment of perivascular cells to newly formed vessels.

Normal angiogenesis is activated during tissue growth, from embryonic development through maturity, and then enters a period of relative quiescence during adulthood.

Normal angiogensesis is also activated during wound healing, and at certain stages of the female reproductive cycle. Inappropriate or pathological angiogenesis has been associated with several disease states including various retinopathies; ischemic disease; atherosclerosis; chronic inflammatory disorders; rheumatoid arthritis, and cancer. The role of angiogenesis in disease states is discussed, for instance, in Fan et al, Trends in Pharmacol Sci. 16:54 66; Shawver et al, DOT Vol. 2, No. 2 Feb. 1997; Folkmann, 1995, Nature Medicine 1:27-31.

In cancer the growth of solid tumors has been shown to be angiogenesis dependent. (See Folkmann, J., J. Nat'l. Cancer Inst., 1990, 82, 4-6.) Consequently, the targeting of pro-angiogenic pathways is a strategy being widely pursued in order to provide new therapeutics in these areas of great, unmet medical need.

Raf is involved in angiogenic processes. Endothelial growth factors (e.g. vascular endothelial growth factor VEGF) activates receptor tyrosine kinases (e.g. VEGFR-2) and signal through the Ras/Raf/Mek/Erk kinase cascade. Activation of VEGFR-2 by VEGF is a critical step in the signal transduction pathway that initiates tumor angiogenesis. VEGF expression may be constitutive to tumor cells and can also be upregulated in response to certain stimuli. One such stimuli is hypoxia, where VEGF expression is upregulated in both tumor and associated host tissues. The VEGF ligand activates VEGFR-2 by binding with its extracellular VEGF binding site. This leads to receptor dimerization of VEGFRs and autophosphorylation of tyrosine residues at the intracellular kinase domain of VEGFR-2. The kinase domain operates to transfer a phosphate from ATP to the tyrosine residues, thus providing binding sites for signaling proteins downstream of VEGFR-2 leading ultimately to initiation of angiogenesis (McMahon, G., The Oncologist, Vol. 5, No. 90001, 3-10, Apr. 2000).

Mice with a targeted disruption in the Braf gene die of vascular defects during development (Wojnowski, L. et al. 1997, Nature genetics 16, page 293-296). These mice show defects in the formation of the vascular system and in angiogenesis e.g. enlarged blood vessels and increased apoptotic death of differentiated endothelial cells.

For the identification of a signal transduction pathway and the detection of cross talks with other signaling pathways suitable models or model systems have been generated by various scientists, for example cell culture models (e.g. Khwaja et al., EMBO, 1997, 16, 2783-93) and transgenic animal models (e.g. White et al., Oncogene, 2001, 20, 7064-7072). For the examination of particular steps in the signal transduction cascade, interfering compounds can be used for signal modulation (e.g. Stephens et al., Biochemical J., 2000, 351, 95-105). The compounds according to the invention may also be useful as reagents for the examination of kinase dependent signal transduction pathways in animal and/or cell culture models or any of the clinical disorders listed throughout this application.

The measurement of kinase activity is a well known technique feasible for each person skilled in the art. Generic test systems for kinase activity detection with substrates, for example histone (e.g. Alessi et al., FEBS Lett. 1996, 399, 3, page 333-8) or myelin basic protein are well described in the literature (e.g. Campos-González, R. and Glenney, Jr., J. R. 1992 J. Biol. Chem. 267, Page 14535).

For the identification of kinase inhibitors various assay systems are available (see for example Walters et al., Nature Drug Discovery 2003, 2; page 259-266). For example, in scintillation proximity assays (e.g. Sorg et al., J. of. Biomolecular Screening, 2002, 7, 11-19) or flashplate assays the radioactive phosphorylation of a protein or peptide as substrate with γATP can be measured. In the presence of an inhibitory compound no signal or a decreased radioactive signal is detectable. Furthermore homogeneous time-resolved fluorescence resonance energy transfer (HTR-FRET), and fluorescence polarization (FP) technologies are useful for assay methods (for example Sills et al., J. of Biomolecular Screening, 2002, 191-214).

Other non-radioactive ELISA based assay methods use specific phospho-antibodies (AB). The phospho-AB binds only the phosphorylated substrate. This binding is detectable with a secondary peroxidase conjugated antibody, measured for example by chemiluminescence (for example Ross et al., Biochem. J., 2002, 366, 977-981).

The present invention provides compounds generally described as glycine amide derivatives, including both aryl and/or heteroaryl derivatives, which are preferably inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p21^(ras), the inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the treatment of human or animal solid cancers, e.g. murine cancer, since the progression of these cancers is dependent upon the ras protein signal transduction cascade and therefore susceptible to treatment by interruption of the cascade, i.e., by inhibiting raf kinase. Accordingly, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered for the treatment of diseases mediated by the raf kinase pathway especially cancers, including solid cancers, such as, for example, carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g., myeloid leukemia) or adenomas (e.g., villous colon adenoma), pathological angiogenesis and metastatic cell migration. Furthermore the compounds are useful in the treatment of complement activation dependent chronic inflammation (Niculescu et al. (2002) Immunol. Res., 24:191-199) and HIV-1 (human immunodeficiency virus type1) induced immunodeficiency (Popik et al. (1998) J Virol, 72: 6406-6413).

Therefore, subject of the present invention are glycinamide derivatives of formula I

A-D-B  (I)

wherein

-   D is a bivalent glycinamide moiety which is bonded to A and B,     preferably to one bonding partner via the N-nitrogen atom and to the     other bonding partner via the N′-nitrogen atom, wherein the     N-nitrogen atom and/or the N′-nitrogen atom is unsubstituted or     substituted with one or more substituents, wherein said substituents     are preferably selected from the group consisting of alkyl,     alkylene, haloalkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkylene,     heterocyclyl, aryl, aralkyl, heteroaryl, hydroxy, alkoxy,     haloalkoxy, aralkoxy, aryloxy, mercapto, alkylsulfanyl,     haloalkylsulfanyl, arylsulfanyl, heteroarylsulfanyl, alkylsulfenyl,     haloalkylsulfenyl, arylsulfenyl, heteroarylsulfenyl, alkylsulfonyl,     haloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, carboxy, cyano,     cyanoalkyl, aminosulfonyl, acyl, acyloxy, carbamoyl, aroyl,     heteroaryl, heteroaroyloxy, unsubstituted amino groups and     substituted amino groups, and wherein the carbonyl group of said     glycine amide moiety can be derivatized, preferably to a C═S, C═NR⁵,     C═C(R⁵)—NO₂, C═C(R⁵)—CN or C═C(CN)₂ group, -   A is a substituted moiety of up to 40 carbon atoms of the formula:     -L-(M-L′)_(α), where L is a 5, 6 or 7 membered cyclic structure,     preferably selected from the group consisting of aryl, heteroaryl,     arylene and heteroarylene, bound directly to D, L′ comprises an     optionally substituted cyclic moiety having at least 5 members,     preferably selected from the group consisting of aryl, heteroaryl,     aralkyl, cycloalkyl and heterocyclyl, M is a bond or a bridging     group having at least one atom, α is an integer of from 1-4; and     each cyclic structure of L and L′ contains 0-4 members of the group     consisting of nitrogen, oxygen and sulfur, wherein Lα is preferably     substituted by at least one substituent which is preferably selected     from the group consisting of —SO_(β)R_(x), —C(O)R_(x) and     —C(NR_(y))R_(z), -   B is a substituted or unsubstituted, up to tricyclic aryl or     heteroaryl moiety of up to 30 carbon atoms, preferably of up to 20     carbon atoms, comprising at least one 5-, 6-, or 7-membered cyclic     structure, preferably a 5- or 6-membered cyclic structure, bound     directly to D containing 0-4 members of the group consisting of     nitrogen, oxygen and sulfur, wherein said cyclic structure directly     bound to D is preferably selected from the group consisting of aryl;     heteroaryl and heterocyclyl, -   R_(y) is hydrogen or a carbon based moiety of up to 24 carbon atoms     optionally containing heteroatoms selected from N, S and O and     optionally halosubstituted, up to per halo, -   R_(z) is hydrogen or a carbon based moiety of up to 30 carbon atoms     optionally containing heteroatoms selected from N, S and O and     optionally substituted by halogen, hydroxy and carbon based     substituents of up to 24 carbon atoms, which optionally contain     heteroatoms selected from N, S and O and are optionally substituted     by halogen; -   R_(x) is R_(z) or NR_(a)R_(b), where R_(a) and R_(b) are     -   a) independently hydrogen, a carbon based moiety of up to 30         carbon atoms optionally containing heteroatoms selected from N,         S and O and optionally substituted by halogen, hydroxy and         carbon based substituents of up to 24 carbon atoms, which         optionally contain heteroatoms, selected from N, S and O, and         are optionally substituted by halogen, or     -    —OSi(R_(f))₃ where R_(f) is hydrogen or a carbon based moiety         of up to 24 carbon atoms optionally containing heteroatoms         selected from N, S and O and optionally substituted by halogen,         hydroxy and carbon based substituents of up to 24 carbon atoms,         which optionally contain heteroatoms selected from N, S and O,         and are optionally substituted by halogen; or     -   b) R_(a) and R_(b) together from a 5-7 member heterocyclic         structure of 1-3 heteroatoms selected from N, S and O, or a         substituted 5-7 member heterocyclic structure of 1-3 heteroatoms         selected from N, S and O substituted by halogen, hydroxy or         carbon based substituents of up to 24 carbon atoms, which         optionally contain heteroatoms selected from N, S and O and are         optionally substituted by halogen; or     -    one of R_(a) or R_(b) is —C(O)—, a C₁-C₅ divalent alkylene         group or a substituted C₁-C₅ divalent alkylene group bound to         the moiety L to form a cyclic structure with at least 5 members,         wherein the substituents of the substituted C₁-C₅ divalent         alkylene group are selected from the group consisting of         halogen, hydroxy, and carbon based substituents of up to 24         carbon atoms, which optionally contain heteroatoms selected from         N, S and O and are optionally substituted by halogen; where B is         substituted, L is substituted or L′ is additionally substituted,         the substituents are selected from the group consisting of         halogen, up to per-halo and Wγ, where γ is 0-3;     -    wherein each W is independently selected from the group         consisting of —CN, —CO₂R, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵,         —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵—NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, -Q-Ar, and         carbon based moieties of up to 24 carbon atoms, optionally         containing heteroatoms selected from N, S and O and optionally         substituted by one or more substituents independently selected         from the group consisting of —CN, —CO₂R, —C(O)NR⁵R⁵, —C(O)—R⁵,         —NO₂, —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵, —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵         and halogen up to per-halo; with each R⁵ independently selected         from H or a carbon based moiety of up to 24 carbon atoms,         optionally containing heteroatoms selected from N, S and O and         optionally substituted by halogen;     -    wherein Q is —O—, —S—, —N(R⁵)—, —(CH₂)_(β), —C(O)—, —CH(OH)—,         —(CH₂)_(β—O—, —(CH) ₂)_(β)—S—, —(CH₂)_(β)N(R⁵)—,         —O(CH₂)_(β)—CHHal-, —CHal₂-, —S—(CH₂)— and —N(R⁵)(CH₂)_(β)—         where β=1-3, and Hal is halogen; and     -    Ar is a 5- or 6-member aromatic structure containing 0-2         members selected from the group consisting of nitrogen, oxygen         and sulfur, which is optionally substituted by halogen, up to         per-halo, and optionally substituted by Z_(δ1) wherein δ1 is 0         to 3 and each Z is independently selected from the group         consisting —CN, —CO₂R⁵, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵,         —NR⁵R⁵, —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, and a carbon based moiety of up         to 24 carbon atoms, optionally containing heteroatoms selected         from N, S and O and optionally substituted by one or more         substituents selected from the group consisting of —CN, —CO₂R⁵,         —C(O)NR⁵R⁵, C(O)—R⁵, —NO₂; —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵,         —NR⁵C(O)OR⁵—NR⁵C(O)R⁵, and with R⁵ as defined above.

More preferred, in the compound of formula I,

-   R_(y) is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₂₋₁₀ alkenyl, C₁₋₁₀     alkenoyl, C₆₋₁₂ aryl, C₃₋₁₂ hetaryl having 1-3 heteroatoms selected     from N, S and O, C₇₋₂₄ aralkyl, C₇₋₂₄ alkaryl, substituted C₁₋₁₀     alkyl, substituted C₁₋₁₀ alkoxy, substituted C₃₋₁₀ cycloalkyl having     0-3 heteroatoms selected from N, S and O, substituted C₆-C₁₄ aryl,     substituted C₃₋₁₂ hetaryl having 1-3 heteroatoms selected from N, S     and O, substituted C₇₋₂₄ alkaryl or substituted C₇₋₂₄ aralkyl, where     Ry is a substituted group, it is substituted by halogen up to per     halo, -   R_(z) is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl     having 0-3 heteroatoms, C₂₋₁₀ alkenyl, C₁₋₁₀ alkenoyl, C₆₋₁₂ aryl,     C₃-C₁₂ hetaryl having 1-3 heteroatoms selected form S, N and O,     C₇₋₂₄ alkaryl, C₇₋₂₄ aralkyl, substituted C₃-C₁₀ cycloalkyl having     0-3 heteroatoms selected from S, N and O, substituted C₃₋₁₂ hetaryl     having 1-3 heteroatoms selected from S, N and O, substituted C₇₋₂₄     alkaryl or substituted C₇-C₂₄ aralkyl where R_(z) is a substituted     group, it is substituted by halogen up to per halo, hydroxy, C₁₋₁₀     alkyl, C₃₋₁₂ cycloalkyl having 0-3 heteroatoms selected from N, S     and O, substituted C₃-C₁₂ hetaryl having 1-3 heteroatoms selected     from N, S and O, C₁₋₁₀ alkoxy, C₆₋₁₂ aryl, C₁₋₆ halo substituted     alkyl up to per halo alkyl, C₆-C₁₂ halo substituted aryl up to per     halo aryl, C₃-C₁₂ halo substituted cycloalkyl up to per halo     cycloalkyl having 0-3 heteroatoms selected from N, S and O, halo     substituted C₃-C₁₂ hetaryl up to per halo, hetaryl having 1-3     heteroatoms selected from O, N and S, halo substituted C₇-C₂₄     aralkyl up to per halo aralkyl, halo substituted C₇-C₂₄ alkaryl up     to per halo alkaryl, and —C(O)R_(g), -   R_(a) and R_(b) are:     -   a) independently hydrogen, a carbon based moiety selected from         the group consisting of C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₃₋₁₀         cycloalkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkenoyl, C₆₋₁₂ aryl, C₃₋₁₂         hetaryl having 1-3 heteroatoms selected from O, N and S, C₃₋₁₂         cycloalkyl having 0-3 heteroatoms selected from N, S and O,         C₇₋₂₄ aralkyl, C₇-C₂₄ alkaryl, substituted C₁₋₁₀ alkyl,         substituted C₁₋₁₀ alkoxy, substituted C₃₋₁₀ cycloalkyl, having         0-3 heteroatoms selected from N, S and O, substituted C₆₋₁₂         aryl, substituted C₃₋₁₂ hetaryl having 1-3 heteroatoms selected         from N, S and O, substituted C₇₋₂₄ aralkyl, substituted C₇₋₂₄         alkaryl; where R_(a) and R_(b) are a substituted group, they are         substituted by halogen up to per halo, hydroxy, C₁₋₁₀ alkyl,         C₃₋₁₂ cycloalkyl having 0-3 heteroatoms selected from O, S and         N, C₃₋₁₂ hetaryl having 1-3 heteroatoms selected from N, S and         O, C₁₋₁₀ alkoxy C₆₋₁₂ aryl, C₁₋₆ halo substituted alkyl up to         per halo alkyl, C₆₋₁₂ halo substituted aryl up to per halo aryl,         C₃-C₁₂ halo substituted cycloalkyl having 0-3 heteroatoms         selected from N, S and O, up to per halo cycloalkyl, halo         substituted C₃-C₁₂ hetaryl up to per halo heteraryl, halo         substituted C₇-C₂₄ aralkyl up to per halo aralkyl, halo         substituted C₇-C₂₄ alkaryl up to per halo alkaryl, and         —C(O)R_(g); or     -    —OSi(R_(f))₃ where R_(f) is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀         alkoxy, C₃₋₁₀ cycloalkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkenoyl; C₆₋₁₂         aryl, C₃₋₁₂ hetaryl having 1-3 heteroatoms selected from O, N         and S, C₃₋₁₂ cycloalkyl having 0-3 heteroatoms selected from N,         S and O, C₇₋₂₄ aralkyl, C₇-C₂₄ alkaryl, substituted C₁₋₁₀ alkyl,         substituted C₁₋₁₀ alkoxy, substituted C₃₋₁₀ cycloalkyl, having         0-3 heteroatoms selected from N, S and O, substituted C₆₋₁₂         aryl, substituted C₃₋₁₂ hetaryl having 1-3 heteroatoms selected         from N, S and O, substituted C₇₋₂₄ aralkyl, substituted C₇₋₂₄         alkaryl, or     -   b) R_(a) and R_(b) together form a 5-7 member heterocyclic         structure of 1-3 heteroatoms selected from N, S and O, or a         substituted 5-7 member heterocyclic structure of 1-3 heteroatoms         selected from N, S and O with substituents selected from the         group consisting of halogen up to per halo, hydroxy, C₁-C₁₀         alkyl, C₁-C₁₀ alkoxy, C₃₋₁₀ cycloalkyl, C₂₋₁₀ alkenyl, C₁₋₁₀         alkenoyl, C₆₋₁₂ aryl, C₃₋₁₂ hetaryl having 1-3 heteroatoms         selected from O, N and S, C₃₋₁₂ cycloalkyl having 0-3         heteroatoms selected from N, S and O, C₇₋₂₄ aralkyl, C₇-C₂₄         alkaryl, substituted C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkoxy,         substituted C₃₋₁₀ cycloalkyl, having 0-3 heteroatoms selected         from N, S and O, substituted C₆₋₁₂ aryl, substituted C₃₋₁₂         hetaryl having 1-3 heteroatoms selected from N, S and O,         substituted C₇₋₂₄ aralkyl, substituted C₇₋₂₄ alkaryl, where         R_(a) and R_(b) are a substituted group, they are substituted by         halogen up to per halo, hydroxy, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl         having 0-3 heteroatoms selected from O, S and N, C₃₋₁₂ hetaryl         having 1-3 heteroatoms selected from N, S and O, C₁₋₁₀ alkoxy,         C₆₋₁₂ aryl, C₁₋₆ halo substituted alkyl up to per halo alkyl,         C₅-C₁₂ halo substituted aryl up to per halo aryl, C₃-C₁₂ halo         substituted cycloalkyl having 0-3 heteroatoms selected from N, S         and O, up to per halo cycloalkyl, halo substituted C₃-C₁₂         hetaryl up to per halo heteraryl, halo substituted C₇-C₂₄         aralkyl up to per halo aralkyl, halo substituted C₇-C₂₄ alkaryl         up to per halo alkaryl, and —C(O)R_(g), or     -   c) one of R_(a) or R_(b) is —C(O)—, a C₁-C₅ divalent alkylene         group or a substituted C₁-C₅ divalent alkylene group bound to         the moiety L to form a cyclic structure with at least 5 members,         wherein the substituents of the substituted C₁-C₅ divalent         alkylene group are selected from the group consisting of         halogen, hydroxy C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl having 0-3         heteroatoms selected from, S, O and N, C₃₋₁₂ hetaryl having 1-3         heteroatoms selected from N, S and O, C₁₋₁₀ alkoxy, C₆₋₁₂ aryl,         C₇-C₂₄ alkaryl, C₇-C₂₄ aralkyl, C₁₋₆ halo substituted alkyl up         to per halo alkyl, C₆-C₁₂ halo substituted aryl up to per halo         aryl, C₃-C₁₂ halo substituted cycloalkyl having 0-3 heteroatoms         selected from N, S and O, up to per halo cycloalkyl, halo         substituted C₃-C₁₂ hetaryl up to per halo heteraryl, halo         substituted C₇-C₂₄ aralkyl up to per halo aralkyl, halo         substituted C₇-C₂₄ alkaryl up to per halo alkaryl, and         C(O)R_(g),     -    where R_(g) is C₁₋₁₀ ally; —CN, —CO₂R_(d), —OR_(d), —SR_(d),         —SO₂R_(d), —SO₃H, —NO₂, —C(O)R_(e), —NR_(d)R_(e),         —NR_(d)C(O)OR_(e) and —NR_(d)(CO)R_(e), and R_(d) and R_(e) are         independently selected from the group consisting of hydrogen,         C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl having 0-3         heteroatoms selected from O, N and S, C₆₋₁₂ aryl, C₃-C₁₂ hetaryl         with 1-3 heteroatoms selected from O, N and S, C₇-C₂₄ aralkyl,         C₇-C₂₄ alkaryl, up to per halo substituted C₁-C₁₀ alkyl, up to         per halo substituted C₃-C₁₀ cycloalkyl having 0-3 heteroatoms         selected from O, N and S, up to per halo substituted C₆-C₁₄         aryl, up to per halo substituted C₃-C₁₂ hetaryl having 1-3         heteroatoms selected from O, N and S, halo substituted C₁-C₂₄         alkaryl up to per halo alkaryl, and up to per halo substituted         C₇-C₂₄-aralkyl, -   W is independently selected from the group consisting —CN, —CO₂R⁵,     —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵,     —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy C₂-C₁₀ alkenyl,     C₁-C₁₀ alkenoyl, C₃-C₁₀ cycloalkyl having 0-3 heteroatoms selected     from O, S and N, C₆-C₁₄ aryl, C₇-C₂₄ alkaryl, C₇-C₂₄ aralkyl, C₃-C₁₂     heteroaryl having 1-3 heteroatoms selected form O, N and S, C₄-C₂₃     alkheteroaryl having 1-3 heteroatoms selected from O, N and S,     substituted C₁-C₁₀ alkyl, substituted C₁-C₁₀ alkoxy, substituted     C₂-C₁₀ alkenyl, substituted C₁-C₁₀ alkenoyl, substituted C₃-C₁₀     cycloalkyl having 0-3 heteroatoms selected from O, N and S,     substituted C₆-C₁₂ aryl, substituted C₃-C₁₂ hetaryl having 1-3     heteroatoms selected from O, N and S, substituted C₇-C₂₄ aralkyl,     substituted C₇-C₂₄ alkaryl, substituted C₄-C₂₃ alkheteroaryl having     1-3 heteroatoms selected from O, N and S, and -Q-Ar; -   R⁵ is independently selected from H, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy     C₂-C₁₀ alkenyl, C₁-C₁₀ alkenoyl, C₃-C₁₀ cycloalkyl having 0-3     heteroatoms selected from O, S and N, C₆-C₁₄ aryl, C₃-C₁₃ hetaryl     having 1-3 heteroatoms selected from O, N and S, C₇-C₁₄ alkaryl,     C₇-C₂₄ aralkyl, C₄-C₂₃ alkheteroaryl having 1-3 heteroatoms selected     from O, N and S, up to per-halosubstituted C₁-C₁₀ alkyl, up to     per-halosubstituted C₃-C₁₀ cycloalkyl having 0-3 heteroatoms     selected from O, N and S, up to per-halosubstituted C₆-C₁₄ aryl, up     to per-halosubstituted C₃-C₁₃ hetaryl having 1-3 heteroatoms     selected from O, N and S, up to per-halosubstituted C₇-C₂₄ aralkyl,     up to per-halosubstituted C₇-C₂₄ alkaryl, and up to     per-halosubstituted C₄-C₂₃ alkheteroaryl; and each -    Z is independently selected from the group consisting —CN, —CO₂R⁵,     —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵,     —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₂-C₁₀     alkenyl, C₁-C₁₀ alkenoyl, C₃-C₁₀ cycloalkyl having 0-3 heteroatoms     selected from O, S and N, C₆-C₁₄ aryl, C₇-C₂₄ alkaryl, C₇-C₂₄     aralkyl, C₃-C₁₂ heteroaryl having 1-3 heteroatoms selected from O, N     and S, C₄-C₂₃ alkheteroaryl having 1-3 heteroatoms selected from O,     N and S, substituted C₁-C₁₀ alkyl, substituted C₁-C₁₀ alkoxy,     substituted C₂-C₁₀ alkenyl, substituted C₁-C₁₀ alkenoyl, substituted     C₃-C₁₀ cycloalkyl having 0-3 heteroatoms selected from O, N and S,     substituted C₆-C₁₂ aryl, substituted C₃-C₁₂ hetaryl having 1-3     heteroatoms selected from O, N and S; wherein if Z is a substituted     group, the one or more substituents are selected from the group     consisting of —CN, —CO₂R⁵, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵,     —SO₂R⁵, —SO₃H, —NR⁵R⁵, —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵.

According to the invention, each M independently from one another represents a bond OR is a bridging group, selected from the group consisting of (CR⁵R⁵)_(h), or (CHR⁵)_(h)-Q-(CHR⁵)_(i), wherein

-   Q is selected from a group consisting of O, S, N—R⁵, (CHal₂)_(j),     (O—CHR⁵)_(j), (CHR⁵—O)_(j), CR⁵═CR⁵, (O—CHR⁵CHR⁵)_(j),     (CHR⁵CHR⁵—O)_(j), C═O, C═S, C═NR⁵, CH(OR⁵), C(OR⁵)(OR⁵), C(═O)O,     OC(═O), OC(═O)O, C(═O)N(R⁵), N(R⁵)C(═O), OC(═O)N(R⁵), N(R⁵C(═O)O,     CH═N—O, CH═N—NR⁵, OC(O)NR⁵, NR⁵C(O)O, S═O, SO₂, O₂NR⁵ and NR⁵SO₂,     wherein -   R⁵ is in each case independently selected from the meanings given     above, preferably from hydrogen, halogen, alkyl, aryl, aralkyl, -   h, i are independently from each other 0, 1, 2, 3, 4, 5 or 6,     preferably 0, 1, 2, or 3, and -   j is 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2 or 3.

More preferred, each M independently from one another represents a bond or is a bridging group, selected from the group consisting of —O—, —S—, —N(R⁵)—, —(CH₂)_(β—, —C(O)—, —CH(OH)—, —(CH) ₂)_(βO—, —(CH) ₂)_(β)S—, —(CH₂)_(β)N(R⁵)—, —O(CH₂)_(β), —CHHal-, —CHal₂-, —S—(CH₂)_(β)— and —N(R⁵)(CH₂)_(β), where β is 1 to 6 and especially preferred 1 to 3, Hal is halogen and R⁵ is as defined above. More preferred, the group B of Formula I is a substituted or unsubstituted six member aryl moiety or six member hetaryl moiety, said hetaryl moiety having 1 to 4 members selected from the group of hetaryl atoms consisting of nitrogen, oxygen and sulfur with the balance of the hetaryl moiety being carbon.

Even more preferred, the group B of Formula I is

-   a) an unsubstituted phenyl group, an unsubstituted pyridyl group, an     unsubstituted pyrimidinyl, a phenyl group substituted by a     substituent selected from the group consisting of halogen and Wγ     wherein W and γ are as defined in claim 1, a pyrimidinyl group     substituted by a substituent selected from the group constituting of     halogen and Wγ, whereas W and γ are as defined above, or a     substituted pyridyl group, substituted by a substituent selected     from the group consisting of halogen and Wγ wherein W and γ are as     defined above; or a substituted phenyl group, a substituted     pyrimidinyl group, or substituted pyridyl group substituted 1 to 3     times by 1 or more substituents selected from the group consisting     of —CN, halogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl alkoxy, —OH, up to per     halo substituted C₁-C₁₀ alkyl, up to per halo substituted C₁-C₁₀     alkoxy or phenyl substituted by halogen up to per halo; or     -   b) a substituted phenyl group, a substituted pyrimidinyl group,         or substituted pyridyl group substituted 1 to 3 times by 1 or         more substituents selected from the group consisting of CN,         halogen, alkyl, especially C₁-C₄ alkyl, alkoxy, especially C₁-C₄         alkoxy, OH, up to per halo substituted alkyl, especially up to         per halo substituted C₁-C₄ alkyl, up to per halo substituted         alkoxy, especially up to per halo substituted C₁-C₄ alkoxy or         phenyl substituted by halogen up to per halo.

In the formula I, the group L which is directly bound to D is preferably a substituted or unsubstituted 6 member aryl moiety or a substituted or unsubstituted 6 member hetaryl moiety, wherein said hetaryl moiety has 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur with the balance of said hetaryl moiety being carbon, wherein the one or more substituents are selected from the group consisting of halogen and Wγ wherein W and γ are as defined above.

More preferred, the group L is a substituted phenyl, unsubstituted phenyl, substituted pyrimidinyl, unsubstituted pyrimidinyl, substituted pyridyl or unsubstituted pyridyl group.

In the formula I, the group L′ preferably comprises a 5 to 6 membered aryl moiety or hetaryl moiety, wherein said heteraryl moiety comprises 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur.

More preferred, the group L′ is phenyl, pyridinyl or pyrimdinyl.

According to the invention, a bivalent glycinamide moiety is preferably a bivalent radical derived from substituted or unsubstituted, preferably unsubstituted amide of the amino acid glycine, or a derivative thereof. If the amide of the amino acid glycine is substituted, it is preferably mono substituted on the nitrogen atom of the amide group and/or mono substituted on the nitrogen atom of the amino group. Preferably, the substituted or unsubstituted amide of the amino acid glycine is bonded to A and B via its nitrogen atoms of the amide group and the amino group, respectively. This kind of linkage is usually referred to as an N,N′-linkage. The hydrogen atoms of one or both nitrogen atoms of the glycine amide moiety can be substituted by suitable substituents, preferably selected from the group consisting of alkyl, alkylene, haloalkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkylene, heterocyclyl, aryl, aralkyl, heteroaryl, carboxy, cyanoalkyl, acyl and heteroaryl. Preferably, both nitrogen atoms of the glycine amide moiety are unsubstituted. Therefore, D is more preferred an unsubstituted amide of the amino acid glycine, which is bonded to the radicals A and B via its N,N′-atoms, or a derivative thereof. In this respect, one or both of the nitrogen atoms of D can, independently from one another, optionally be deprotonated, protonated and/or quarternized. The resulting ions or salts are also subject of the present invention. Derivatives of the glycine amide moiety according to the invention are preferably derivatives, wherein the carbonyl group of said glycine amide moiety is derivatized to a C═S, C═NR⁵, C═C(R⁵)—NO₂, C═C(R⁵)—CN or C═C(CN)₂ group.

Accordingly, preferred compounds of formula I are of formula Ia and/or Ib

wherein A and B are as defined above/below, Y is selected from O, S, NR⁵, C(R⁵)—NO₂, C(R⁵)—CN and C═C(CN)₂, and wherein R⁶ and R⁷ are independently selected from the group consisting of H, alkyl, alkylene, haloalkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkylene, heterocyclyl, aryl, aralkyl, heteroaryl, carboxy, cyanoalkyl, acyl and heteroaryl, and the salts or solvates thereof. More preferred are compounds of formula Ia and/or Ib, wherein Y is O and/or wherein one or both of the residues R⁶ and R⁷ are H, and the salts or solvates thereof.

Accordingly, one aspect of the instant invention relates to compounds of formula Ic and/or Id,

wherein A and B are as defined above/below, and the salts or solvates thereof.

As used herein, the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, heating, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

As used herein, the term “alkyl” preferably refers to a straight or branched chain hydrocarbon having from one to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of C₁-C₁₀ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆ alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or C₁-C₆ perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.

As used herein, the term “C₁-C₆ alkyl” preferably refers to an alkyl group as defined above containing at least 1, and at most 6, carbon atoms. Examples of branched or straight chained “C₁-C₆ alkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl and isopentyl.

As used herein, the term “alkylene” preferably refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group which includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl, optionally substituted by alkyl, nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene and the like.

As used herein, the term “C₁-C₆ alkylene” preferably refers to an alkylene group, as defined above, which contains at least 1, and at most 6, carbon atoms respectively. Examples of “C₁-C₆ alkylene” groups useful in the present invention include, but are not limited to, methylene, ethylene and n-propylene.

As used herein, the term “halogen” or “hal” preferably refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

As used herein, the term “C₁-C₆ haloalkyl” preferably refers to an alkyl group as defined above containing at least 1, and at most 6, carbon atoms substituted with at least one halogen, halogen being as defined herein. Examples of branched or straight chained “C₁-C₆ haloalkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo and Iodo.

As used herein, the term “C₃-C₇ cycloalkyl” preferably refers to a non-aromatic cyclic hydrocarbon ring having from three to seven carbon atoms and which optionally includes a C₁-C₆ alkyl linker through which it may be attached. The C₁-C₆ alkyl group is as defined above. Exemplary “C₃-C₇ cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, the term “C₃-C₇ cycloalkylene” preferably refers to a non-aromatic alicyclic divalent hydrocarbon radical having from three to seven carbon atoms, optionally substituted with substituents selected from the group which includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “cycloalkylene” as used herein include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.

As used herein, the term “heterocyclic” or the term “heterocyclyl” preferably refers to a three to twelve-membered heterocyclic ring having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, SO₂, O or N, optionally substituted with substituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆ haloalkylsulfanyl, C₁-C₆ alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or C₁-C₆ perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more other “heterocyclic” ring(s) or cycloalkyl ring(s). Examples of “heterocyclic” moieties include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, pyrrolidine, piperidine, morpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.

As used herein, the term “heterocyclylene” preferably refers to a three to twelve-membered heterocyclic ring diradical having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO₂, O or N, optionally substituted with substituents selected from the group which includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more benzene rings or to one or more of another “heterocyclic” rings or cycloalkyl rings. Examples of “heterocyclylene” include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, and the like.

As used herein, the term “aryl” preferably refers to an optionally substituted benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings to form, for example, anthracene, phenanthrene, or napthalene ring systems. Exemplary optional substituents include C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆ alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, C₁-C₆ perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed. Examples of “aryl” groups include, but are not limited to Phenyl, 2-naphthyl, 1-naphthyl, biphenyl, as well as substituted derivatives thereof.

As used herein, the term “arylene” preferably refers to a benzene ring diradical or to a benzene ring system diradical fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group which includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl and aryl, multiple degrees of substitution being allowed. Examples of “arylene” include, but are not limited to benzene-1,4-diyl, naphthalene-1,8-diyl, anthracene-1,4-diyl, and the like.

As used herein, the term “aralkyl” preferably refers to an aryl or heteroaryl group, as defined herein, attached through a C₁-C₆ alkyl linker, wherein C₁-C₆ alkyl is as defined herein. Examples of “aralkyl” include, but are not limited to, benzyl, phenylpropyl, 2-pyridylmethyl, 3-isoxazolylmethyl, 5-methyl-3-isoxazolylmethyl and 2-imidazolylethyl.

As used herein, the term “heteroaryl” preferably refers to a monocyclic five to seven-membered aromatic ring, or to a fused bicyclic aromatic ring system comprising two of such monocyclic five to seven-membered aromatic rings. These hetroaryl rings contain one or more nitrogen, sulfur and/or oxygen heteroatoms, where N-Oxides and sulfur Oxides and dioxides are permissible heteroatom substitutions and may be optionally substituted with up to three members selected from a group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆ haloalkylsulfanyl, C₁-C₆ alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, C₁-C₆ perfluoroalkyl, heteroaryl or aryl, multiple degrees of substitution being allowed. Examples of “heteroaryl” groups used herein include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, and substituted versions thereof. As used herein, the term “heteroarylene” preferably refers to a five- to seven-membered aromatic ring diradical, or to a polycyclic heterocyclic aromatic ring diradical, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-Oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed. For polycyclic aromatic ring system diradicals, one or more of the rings may contain one or more heteroatoms. Examples of “heteroarylene” used herein are furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the like.

As used herein, the term “alkoxy” preferably refers to the group R_(a)O—, where R_(a) is alkyl as defined above and the term “C₁-C₆ alkoxy” preferably refers to an alkoxy group as defined herein wherein the alkyl moiety contains at least 1 and at most 6 carbon atoms. Exemplary C₁-C₆ alkoxy groups useful in the present invention include, but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and t-butoxy.

As used herein, the term “haloalkoxy” preferably refers to the group R_(a)O—, where R_(a) is haloalkyl as defined above and the term “C₁-C₆ haloalkoxy” preferably refers to an haloalkoxy group as defined herein wherein the haloalkyl moiety contains at least 1 and at most 6 carbon atoms. Exemplary C₁-C₆ haloalkoxy groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and t-butoxy substituted with one or more halo groups, for instance trifluoromethoxy.

As used herein the term “aralkoxy” preferably refers to the group R_(C)R_(B)O—, where R_(B) is alkyl and R_(C) is aryl as defined above.

As used herein the term “aryloxy” preferably refers to the group R_(C)O—, where R^(C) is aryl as defined above.

As used herein, the term “alkylsulfanyl” preferably refers to the group R_(A)S—, where R_(A) is alkyl as defined above and the term “C₁-C₆ alkylsulfanyl” preferably refers to an alkylsulfanyl group as defined herein wherein the alkyl moiety contains at least 1 and at most 6 carbon atoms.

As used herein, the term “haloalkylsulfanyl” preferably refers to the group R_(D)S—, where R_(D) is haloalkyl as defined above and the term “C₁-C₆ haloalkylsulfanyl” preferably refers to a haloalkylsulfanyl group as defined herein wherein the alkyl moiety contains at least 2 and at most 6 carbon atoms.

As used herein, the term “alkylsulfenyl” preferably refers to the group R_(A)S(O)—, where R_(A) is alkyl as defined above and the term “C₁-C₆ alkylsulfenyl” preferably refers to an alkylsulfenyl group as defined herein wherein the alkyl moiety contains at least 1 and at most 6 carbon atoms.

As used herein, the term “alkylsulfonyl” preferably refers to the group R_(A)SO₂—, where R_(A) is alkyl as defined above and the term “C₁-C₆ alkylsulfonyl” preferably refers to an alkylsulfonyl group as defined herein wherein the alkyl moiety contains at least 1 and at most 6 carbon atoms.

As used herein, the term “oxo” preferably refers to the group ═O.

As used herein, the term “mercapto” preferably refers to the group —SH.

As used herein, the term “carboxy” preferably refers to the group —COOH.

As used herein, the term “cyano” preferably refers to the group —CN.

As used herein, the term “cyanoalkyl” preferably refers to the group —R_(B)CN, wherein R_(B) is alkylen as defined above. Exemplary “cyanoalkyl” groups useful in the present invention include, but are not limited to, cyanomethyl, cyanoethyl and cyanoisopropyl.

As used herein, the term “aminosulfonyl” preferably refers to the group —SO₂NH₂.

As used herein, the term “carbamoyl” preferably refers to the group —C(O)NH₂.

As used herein, the term, “sulfanyl” shall refer to the group —S—.

As used herein, the term “sulfenyl” shall refer to the group —S(O)—.

As used herein, the term “sulfonyl” shall refer to the group —S(O)₂— or —SO₂—.

As used herein, the term “acyly” preferably refers to the group R_(F)C(O)—, where R_(F) is alkyl, cycloalkyl or heterocyclyl as defined herein.

As used herein, the term “aryl” preferably refers to the group R_(C)C(O)—, where R_(C) is aryl as defined herein.

As used herein, the term “heteroaroyl” preferably refers to the group R_(E)C(O)—, where R_(E) is heteroaryl as defined herein.

As used herein, the term “alkoxycarbonyl” preferably refers to the group R_(A)OC(O)—, where R_(A) is alkyl as defined herein.

As used herein, the term “acyloxy” preferably refers to the group R_(F)C(O)O—, where R_(F) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aryloxy” preferably refers to the group R_(C)C(O)O—, where R_(C) is aryl as defined herein.

As used herein, the term “heteroaroyloxy” preferably refers to the group R_(E)C(O)O—, where R_(E) is heteroaryl as defined herein.

As used herein, the term “carbonyl” or “carbonyl moiety” preferably refers to the group C═O.

As used herein, the term “thiocarbonyl” or “thiocarbonyl moiety” preferably refers to the group C═S.

As used herein, the term “amino”, “amino group” or “amino moiety” preferably refers to the group NR_(G)R_(G′), wherein R_(G) and R_(G′), are preferably selected, independently from one another, from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, cyanoalkyl, aryl, aralkyl, heteroaryl, acyl and aroyl. If both R_(G) and R_(G′) are hydrogen, NR_(G)R_(G′) is also referred to as “unsubstituted amino moiety” or “unsubstituted amino group”. If R_(G) and/or R_(G′) are other than hydrogen, NR_(G)R_(G′) is also referred to as “substituted amino moiety” or “substituted amino group”.

As used herein, the term “imino” or “imino moiety” preferably refers to the group C═NR_(G), wherein R_(G) is preferably selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, cyanoalkyl, aryl, aralkyl, heteroaryl, acyl and aroyl. If R_(G) is hydrogen C═NR_(G) is also referred to as “unsubstituted imino moiety”. If R_(G) is a residue other than hydrogen, C═NR_(G) is also referred to as “substituted imino moiety”.

As used herein, the term “ethene-1,1-diyl moiety” preferably refers to the group C═CR_(K)R_(L), wherein R_(K) and R_(L) are preferably selected, independently from one another, from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, nitro, alkylenecycloalkyl, cyanoalkyl, aryl, aralkyl, heteroaryl, acyl and aroyl. If both hydrogen R_(K) and R_(L) are hydrogen, C═CR_(K)R_(L) is also referred to as “unsubstituted ethene-1,1-diyl moiety”. If one of R_(K) and R_(L) or both are a residue other than hydrogen, C═CR_(K)R_(L) is also referred to as “substituted ethene-1,1-diyl moiety”.

As used herein, the terms “group”, “residue” and “radical” or “groups”, “residues” and “radicals” are usually used as synonyms, respectively, as it is common practice in the art.

As used herein, the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.

As used herein, the term “physiologically functional derivative” preferably refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.

As used herein, the term “solvate” preferably refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula I or formula II or a salt or physiologically functional derivative thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.

As used herein, the term “substituted” preferably refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.

Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two or more stereoisomers, which are usually enantiomers and/or diastereomers. Accordingly, the compounds of this invention include mixtures of stereoisomers, especially mixtures of enantiomers, as well as purified stereoisomers, especially purified enantiomers, or stereoisomerically enriched mixtures, especially enantiomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formulae I and II above as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral Centers are inverted. Also, it is understood that all tautomers and mixtures of tautomers of the compounds of formulae (I) or (II) are included within the scope of the compounds of formulae (I) and (II) and preferably the formulae and subformulae corresponding thereto.

Racemates obtained can be resolved into the isomers mechanically or chemically by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Also advantageous is enantiomer resolution with the aid of a column filled with an optically active resolving agent (for example dinitrobenzoylphenylglycine); an example of a suitable eluent is a hexane/isopropanol/acetonitrile mixture.

The diastereomer resolution can also be carried out by standard purification processes, such as, for example, chromatography or fractional crystallization.

It is of course also possible to obtain optically active compounds of the formula I or II by the methods described above by using starting materials which are already optically active.

Unless indicated otherwise, it is to be understood that reference to compounds of formula I preferably includes the reference to the compounds formulae Ia to Id and/or of formula II. Unless indicated otherwise, it is to be understood that reference to the compounds of formula II preferably includes the reference to the sub formulae corresponding thereto, for example the sub formulae II.1 to II.20 and preferably formulae IIa to IIh. It is also understood that the following embodiments, including uses and compositions, although recited with respect to formula I are preferably also applicable to formulae II, sub formulae II.1 to II.20 and preferably formulae IIa to IIh.

Especially preferred compounds according to the invention are compounds of formula II

wherein

-   Ar¹, Ar² are selected independently from one another from aromatic     hydrocarbons containing 6 to 14 carbon atoms and ethylenical     unsaturated or aromatic heterocyclic residues containing 3 to 10     carbon atoms and one or two heteroatoms, independently selected from     N, O and S, -   R⁸, R⁹ and R¹⁰ are independently selected from a group consisting of     H, A, cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH₂Hal,     CH(Hal)₂, C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹²,     (CH₂)_(n)OR¹¹, (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COOR¹²,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)NR¹¹COR¹³, (CH₂)_(n)NR¹¹CONR¹¹R¹²,     (CH₂)_(n)NR¹¹SO₂A, (CH₂)_(n)SO₂NR¹¹R¹², (CH₂)_(n)S(O)_(u)R¹³,     (CH)_(n)OC(O)R¹³, (CH₂)_(n)COR¹³, (CH₂)_(n)SR¹¹, CH═N—OA,     CH₂CH═N—OA, (CH₂)_(n)NHOA, (CH₂)_(n)CH═N—R¹¹, (CH₂)_(n)OC(O)NR¹¹R¹²,     (CH₂)_(n)NR¹¹COOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂OR¹³,     (CH₂)_(n)N(R¹¹)CH₂CH₂OCF₃, (CH₂)_(n)N(R¹¹)C(R¹³)HCOOR¹²,     C(R¹³)HCOR¹⁴, (CH₂)_(n)N(R¹¹)CH₂CH₂N(R¹²)CH₂COOR¹²,     (CH₂)_(n)N(R¹¹)CH₂CH₂NR¹¹R¹², CH═CHCOOR¹¹, CH═CHCH₂NR¹¹R¹²,     CH═CHCH₂NR¹¹R¹², CH═CHCH₂OR¹³, (CH₂)_(n)(COOR¹¹)COOR¹²,     (CH₂)_(n)N(CONH₂)COOR¹¹, (CH₂)_(n)N(CONH₂)CONH₂,     (CH₂)_(n)N(CH₂COOR¹¹)COOR¹², (CH₂)_(n)N(CH₂CONH₂)COOR¹¹,     (CH₂)_(n)N(CH₂CONH₂)CONH₂, (CH₂)_(n)CHR¹³COR¹⁴,     (CH₂)_(n)CHR¹³COOR¹¹, (CH₂)_(n)CHR¹³CH₂OR¹¹, (CH₂)_(n)OCN and     (CH₂)_(n)NCO, wherein -   R¹¹, R¹² are independently selected from a group consisting of H, A,     (CH₂)_(m)Ar³ and (CH₂)_(m)Het, or in NR¹¹R¹², -   R¹¹ and R¹² form, together with the N-Atom they are bound to, a S—,     6- or 7-membered heterocyclus which additionally contains 1 or 2     hetero atoms, selected from N, O an S, -   R¹³, R¹⁴ are independently selected from a group consisting of H,     Hal, A, (CH₂)_(m)Ar⁴ and (CH₂)_(m)Het, -   A is selected from the group consisting of alkyl, alkenyl,     cycloalkyl, alkylenecycloalkyl, alkoxy and alkoxyalkyl, -   Ar³, Ar⁴ are independently from one another aromatic hydrocarbon     residues comprising 5 to 12 and preferably 5 to 10 carbon atoms     which are optionally substituted by one or more substituents,     selected from a group consisting of A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶,     COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵,     SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵, -   Het is a saturated, unsaturated or aromatic heterocyclic residue     which is optionally substituted by one or more substituents,     selected from a group consisting of A, Hal, NR¹⁵COR¹⁶,     NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵, SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵, -   R¹⁵, R¹⁶ are independently selected from a group consisting of H, A,     and (CH₂)_(m)Ar⁶, wherein -   Ar⁶ is a 5- or 6-membered aromatic hydrocarbon which is optionally     substituted by one or more substituents selected from a group     consisting of methyl, ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN,     OH, NH₂ and CF₃, -   k, m and n are independently of one another 0, 1, 2, 3, 4, or 5, -   X represents a bond or is (CR¹¹R¹²)_(h), or     (CHR¹¹)_(h)-Q-(CHR¹²)_(i), wherein -   Q is selected from a group consisting of O, S, N—R¹⁵, (CHal₂)_(j),     (O—CHR¹⁸)_(j), (CHR⁸—O)_(j), CR¹⁸═CR¹⁹, (O—CHR¹⁸CHR¹⁹)_(j),     (CHR¹⁸CHR¹⁹—O)_(j), C═O, C═S, C═NR¹⁵, CH(OR¹⁵), C(OR¹⁵)(OR²⁰),     C(═O)O, OC(—O), OC(═O)O, C(═O)N(R¹⁵), N(R¹⁵)C(═O), OC(—O)N(R¹⁵),     N(R¹⁵)C(═O)O, CH═N—O, CH═N—NR¹⁵, S═O, SO₂, SO₂NR¹⁵ and NR¹⁵SO₂,     wherein -   R¹⁸, R¹⁹, R²⁰ are independently selected from the meanings given for     R⁸, R⁹ and R¹⁰, preferably independently selected from the group     consisting of H, A, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)OR¹¹, (CH₂)_(n)NR¹¹R¹²,     (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COOR¹¹, (CH₂)_(n)CONR¹¹R¹²,     (CH₂)_(n)NR¹¹COR¹³, (CH₂)_(n)NR¹¹CONR¹¹R¹², (CH₂)_(n)NR¹¹SO₂A,     (CH₂)_(n)SO₂NR¹¹R¹², (CH₂)_(n)S(O)_(u)R¹³, (CH₂)_(n)COR¹³,     (CH₂)_(n)SR¹¹, (CH₂)_(n)NHOA and (CH₂)_(n)NR¹¹COOR¹², -   h, i are independently from each other 0, 1, 2, 3, 4, 5, or 6, and -   j is 1, 2, 3, 4, 5, or 6, -   Y is selected from O, S, NR²¹, C(R²²)—NO₂, C(R²²)—CN and C(CN)₂,     wherein -   R²¹ is independently selected from the meanings given for R¹³, R¹⁴     and -   R²² is independently selected from the meanings given for R¹¹, R¹², -   p, r are independently from one another 0, 1, 2, 3, 4 or 5, -   q is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, -   u is 0, 1, 2 or 3, preferably Q, 1 or 2, and -   Hal is independently selected from a group consisting of F, Cl, Br     and I;     and the salts and solvates thereof, preferably the physiologically     acceptable salts and solvates thereof.

Even more preferred are compounds of formula II

wherein

-   Ar¹, Ar² are selected independently from one another from aromatic     hydrocarbons containing 6 to 10 and especially 6 carbon atoms and     ethylenical unsaturated or aromatic heterocyclic residues containing     3 to 8 and especially 4 to 6 carbon atoms and one or two     heteroatoms, independently selected from N, O and S and especially     selected from N and O, -   R⁸, R⁹ and R¹⁰ are independently selected from a group consisting of     H, A, cycloalkyl 3 to 7 carbon atoms, Hal, CH₂Hal, CH(Hal)₂,     C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)OR¹¹, (CH₂)_(n)NR¹¹R¹²     (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹¹, (CH₂)_(n)CONR¹¹R¹²,     (CH₂)_(n)NR¹¹COR¹³, (CH₂)_(n)NR¹¹CONR¹¹R¹², (CH₂)_(n)NR¹¹SO₂A,     (CH₂)_(n)SO₂NR¹¹R¹², (CH₂)_(n)S(O)_(u)R¹³, (CH₂)_(n)OC(O)R¹³,     (CH₂)_(n)COR¹³, (CH₂)_(n)SR¹¹, (CH₂)_(n)NHOA, (CH₂)_(n)NR¹¹COOR¹²,     (CH₂)_(n)N(R¹¹)CH₂CH₂OR¹³, (CH₂)_(n)N(R¹¹)CH₂CH₂OCF₃,     (CH₂)_(n)N(R¹¹)C(R¹³)HCOOR¹², (CH₂)_(n)N(R¹¹)C(R¹³)HCOR¹³,     (CH₂)_(n)N(COOR¹³)COOR¹⁴, (CH₂)_(n)N(CONH₂)COOR¹¹,     (CH₂)_(n)N(CONH₂)CONH₂, (CH₂)_(n)N(CH₂COOR¹¹)COOR¹²,     (CH₂)_(n)N(CH₂CONH₂)COOR¹¹, (CH₂)_(n)N(CH₂CONH₂)CONH₂,     (CH₂)_(n)COHR¹³COR¹⁴, (CH₂)_(n)CHR¹³COOR¹² and     (CH₂)_(n)CHR¹³CH₂OR¹⁴, -   X represents a bond or is (CR¹¹R¹²)_(h), or     (CHR¹¹)_(h)-Q-(CHR¹²)_(i), wherein -   Q is selected from a group consisting of O, S, N—R¹⁵, (CHal₂)_(j),     (O—CHR¹⁸)_(j), (CHR¹⁸—O)_(j), CR¹⁸═CR¹⁹, (O—CHR¹⁸CHR¹⁹)_(j),     (CHR¹⁸CHR¹⁹—O)_(j), C═O, C═NR¹⁵, CH(OR¹⁵), C(OR¹⁵)(OR²⁰),     C(═O)N(R¹⁵), N(R¹⁵)C(═O), CH═N—NR¹⁵, S═O, SO₂, SO₂NR¹⁵ and NR¹⁵SO₂,     wherein -   h, i are independently from each other 0, 1, 2, 3, 4, 5 or 6,     preferably 0, 1, 2 or 3 and -   j is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, -   p is 1, 2, 3 or 4, preferably 1, 2 or 3, and -   r is 0, 1, 2, or 3, preferably 0, 1 or 2;     and the salts and solvates thereof, preferably the physiologically     acceptable salts and solvates thereof.

Subject of the present invention are especially compounds of formula I and II, in which one or more substituents or groups, preferably the major part of the substituents or groups has a meaning which is indicated as preferred, more preferred, even more preferred or especially preferred.

In compounds of formula II, the term alkyl preferably refers to an unbranched or branched alkyl residue, preferably an unbranched alkyl residue comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1, 2, 3, 4, 5 or 6, more preferred 1, 2, 3 or 4 and especially i or 2 carbon atoms, or a branched alkyl residue comprising 3, 4, 5, 6, 7, 8, 9 or 10, preferably 3, 4, 5 or 6 more preferred 3 or 4 carbon atoms. The alkyl residues can be optionally substituted, especially by one or more halogen atoms, for example up to perhaloalkyl, by one or more hydroxy groups or by one or more amino groups, all of which can optionally be substituted by alkyl. If an alkyl residue is substituted by halogen, it usually comprises 1, 2, 3, 4 or 5 halogen atoms, depending on the number of carbon atoms of the alkyl residue. For example, a methyl group can comprise, 1, 2 or 3 halogen atoms, an ethyl group (an alkyl residue comprising 2 carbon atoms) can comprise 1, 2, 3, 4 or 5 halogen atoms. If an alkyl residue is substituted by hydroxy groups, it usually comprises one or two, preferably one hydroxy groups. If the hydroxy group is substituted by alkyl, the alkyl substituent comprises preferably 1 to 4 carbon atoms and is preferably unsubstituted or substituted by halogen and more preferred unsubstituted. If an alkyl residue is substituted by amino groups, it usually comprises one or two, preferably one amino groups. If the amino group is substituted by alkyl, the alkyl substituent comprises preferably 1 to 4 carbon atoms and is preferably unsubstituted or substituted by halogen and more preferred unsubstituted. According to compounds of formula II, alkyl is preferably selected from the group consisting of methyl, ethyl, trifluoro methyl, pentafluoro ethyl, isopropyl, tert.-butyl, 2-amino ethyl, N-methyl-2-amino ethyl, N,N-dimethyl-2-amino ethyl, N-ethyl-2-amino ethyl, N,N-diethyl-2-amino ethyl, 2-hydroxy ethyl, 2-methoxy ethyl and 2-ethoxy ethyl, further preferred of the group consisting of 2-butyl, n-pentyl, neo-nentyl, isopentyl, hexyl and n-decyl, more preferred of methyl, ethyl, trifluoro methyl, isoproply and tert.-butyl.

In compounds of formula II, alkenyl is preferably selected from the group consisting of allyl, 2- or 3-butenyl, isobutenyl, sec-butenyl, furthermore preferably 4-pentenyl, isopentenyl and 5-hexenyl.

In compounds of formula II, alkylene is preferably unbranched and is more preferably methylene or ethylene, furthermore preferably propylene or butylene.

In compounds of formula II, alkylenecycloalkyl preferably has 5 to 10 carbon atoms and is preferably methylenecyclopropyl, methylenencyclobutyl, furthermore preferably methylenecyclopentyl, methylenecyclohexyl or methylenecycloheptyl, furthermore alternatively ethylenecyclopropyl, ethylenecyclobutyl, ethylenecyclopentyl, ethylenecyclohexyl or ethylenencycloheptyl, propylenecyclopentyl, propylenecyclohexyl, butylenecyclopentyl or butylenecyclohexyl.

In compounds of formula II, the term “alkoxy” preferably comprises groups of formula O-alkyl, where alkyl is an alkyl group as defined above. More preferred, alkoxy is selected from group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, 2-butoxy, tert.-butoxy and halogenated, especially perhalogenated, derivatives thereof. Preferred perhalogenated derivatives are selected from the group consisting of O—CCl₃, O—CF₃, O—C₂Cl₅, O—C₂F₅, O—C(CCl₃)₃ and O—C(CF₃)₃.

In compounds of formula II, the term “alkoxyalkyl” preferably comprises branched and unbranched residues, more preferred unbranched residues, of formula C_(u)H_(2u+1)—O—(CH₂)_(v), wherein u and v are independently from each other 1 to 6. Especially preferred is u=1 and v=1 to 4.

In compounds of formula II the term “alkoxyalkyl” includes alkoxyalkyl groups as defined above, wherein one or more of the hydrogen atoms are substituted by halogen, for example up to perhalo alkoxyalkyl.

In compounds of formula II, cycloalkyl preferably has 3-7 carbon atoms and is preferably cyclopropyl or cyclobutyl, furthermore preferably cyclopentyl or cyclohexyl, furthermore also cycloheptyl, particularly preferably cyclopentyl.

In compounds of formula II, Ar³ to Ar⁶ are preferably selected independently from one another from phenyl, naphthyl and biphenyl which is optionally substituted by one or more substituents, selected from the group consisting of A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶, COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵, SO₂R¹⁵R¹⁶, S(O)_(u)A and OOR¹⁵.

In compounds of formula II, het is preferably an optionally substituted aromatic heterocyclic residue and even more preferred and optionally substituted saturated heterocyclic residue, wherein the substituents are preferably selected from A, CN and Hal. Even more preferred, het is selected from the group consisting of 1-piperidyl, 1-piperazyl, 1-(4-methyl)-piperazyl, 4-methylpiperazin-1-yl amine, 4-morpholinyl, 1-4pyrrolidinyl, 1-pyrazolidinyl 1-(2-methyl)-pyrazolidinyl, 1-imidazolidinyl or 1-(3-methyl)-imidazolidinyl, thiophen-2-yl, thiophen-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, chinolinyl, isochinolinyl, 2-pyridazyl, 4-pyridazyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazinyl and 3-pyrazinyl.

Preferably, the sum of h and l exceeds 0.

A preferred aspect of the instant invention relates to compounds of formula II, wherein n is 0 or 1 and especially 0.

Another preferred aspect of the instant invention relates to compounds of formula II, wherein n is 0 in the residues R⁸, R⁹ and/or R¹⁰ and especially in R¹⁰.

Another preferred aspect of the instant invention relates to compounds of formula II, wherein X represents a bridging group, selected from (CR¹¹R¹²)_(h) or (CHR¹¹)_(h)-Q-(CHR¹²)_(i).

The invention relates in particular to compounds of the formula II in which at least one of said radicals has one of the preferred meanings given above.

Some mere preferred groups of compounds may be expressed by the following sub-formulae II.1) to II.20), which correspond to the formula II and in which radicals not denoted in greater detail are as defined in the formula II, but in which

-   II.1) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or     imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and     especially phenyl or oxazolyl; -   II.2) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or     imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and     especially phenyl or oxazolyl, and -    p is 1, 3 or 3; -   II.3) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or     imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and     especially phenyl or oxazolyl, -    p is 1, 2 or 3, and -    R⁸ is selected from the group consisting of alkyl comprising 1 to 4     carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH₂Hal,     CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₁₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³; -   II.4) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or     imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and     especially phenyl or oxazolyl, -    p is 1, 2 or 3, -    R⁸ is selected from the group consisting of alkyl comprising 1 to 4     carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH₂Hal,     CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³; -   II.5) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or     imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and     especially phenyl or oxazolyl, -    p is 1, 2 or 3, -    R⁸ is selected from the group consisting of alkyl comprising 1 to 4     carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH₂Hal,     CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(r)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     wherein -    n is 0 or 1; -   II.6) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or     imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and     especially phenyl or oxazolyl, -    p is 1, 2 or 3, -    R⁸ is selected from the group consisting of alkyl comprising 1 to 4     carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH₂Hal,     CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(r)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     wherein -    n is 0 or 1, and -    E, is 0; -   II.7) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or     imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and     especially phenyl or oxazolyl, -    p is 1, 2 or 3, -    R⁸ is selected from the group consisting of alkyl comprising 1 to 4     carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH₂Hal,     CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     wherein -    n is 0 or 1, -    u is 0 or 2, preferably 0, and -    q is 0 or 1, and -    X is selected from the group consisting of O, S, NR¹⁵, CHOR¹¹, CH₂,     CH₂OH₂, OCH₂, CH₂O, OCH₂OH₂, CH₂CH₂O, preferably O, S and CH₂ and     especially O and S; -   II.8) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or     imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and     especially phenyl or oxazolyl, -    p is 1, 2 or 3, -    R⁸ is selected from the group consisting of alkyl comprising 1 to 4     carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH₂Hal,     CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     wherein -    n is 0 or 1, -    u is 0 or 2, preferably 0, and -    q is 0 or 1, and -    X is selected from the group consisting of O, S, NR¹⁵, CHOR¹¹, CH₂     CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and CH₂ and     especially O and S, -    Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl or     pyridinyl; -   II.9) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or     imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and     especially phenyl or oxazolyl, -    p is 1, 2 or 3, -    R⁸ is selected from the group consisting of alkyl comprising 1 to 4     carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH₂Hal,     CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     wherein -    n is 0 or 1, -    u is 0 or 2, preferably 0, and -    q is 0 or 1, and -    X is selected from the group consisting of O, S, NR¹⁵, CHOR¹¹, CH₂,     CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and CH₂ and     especially O and S, -    Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl or     pyridinyl, and -    R¹⁰ is selected from the group consisting of H, alkyl comprising 1     to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(t)—O—(CH₂)_(k)NR¹¹R¹²,     (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹, (CH₂)_(n)CONR¹¹R¹²,     (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably selected     from the group consisting of alkyl comprising 1 to 4 carbon atoms,     (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³,     (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially     (CH₂)_(n)CONR¹¹R¹²; -   II.10) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or     imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and     especially phenyl or oxazolyl, -    p is 1, 2 or 3, -    R⁸ is selected from the group consisting of alkyl comprising 1 to 4     carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH₂Hal,     CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     wherein -    n is 0 or 1, -    u is 0 or 2, preferably O, and -    q is 0 or 1 and -    X is selected from the group consisting of O, S, NR¹⁵, CHOR¹¹, CH₂,     CH₂CH₂OCH₂, CH₂, OCH₂CH₂, CH₂CH₂O, preferably O, S and CH₂ and     especially O and S, -    Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl or     pyridinyl, and -    R¹⁰ is selected from the group consisting of H, alkyl comprising 1     to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,     (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹, (CH₂)_(n)CONR¹¹R¹²,     (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably selected     from the group consisting of alkyl comprising 1 to 4 carbon atoms,     (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³,     (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially     (CH₂)_(n)CONR¹¹R¹², wherein -    n is 0, 1 or 2, preferably 0 or 1; -   II.11) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or     imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and     especially phenyl or oxazolyl, -    p is 1, 2 or 3, -    R⁸ is selected from the group consisting of alkyl comprising 1 to 4     carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH₂Hal,     CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     wherein -    n is 0 or 1, -    u is 0 or 2, preferably 0, and -    q is 0 or 1, and -    X is selected from the group consisting of O, S, NR¹⁵, CHOR¹¹, CH₂,     CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and CH₂ and     especially O and S, -    Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl or     pyridinyl, and -    R¹⁰ is selected from the group consisting of H, alkyl comprising 1     to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,     (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹, (CH₂)_(n)CONR¹¹R¹²,     (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably selected     from the group consisting of alkyl comprising 1 to 4 carbon atoms,     (CH₂)_(n)NP¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³,     (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially     (CH₂)_(n)CONR¹¹R¹², wherein -    n is 0, 1 or 2, preferably 0 or 1 and -    r is 0, 1 or 2, preferably 0 or 1; -   II.12) p is 1, 2 or 3, -    R⁸ is selected from the group consisting of alkyl comprising 1 to 4     carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH₂Hal,     CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     wherein -    n is 0 or 1, -    u is 0 or 2, preferably 0, and -    q is 0 or 1, and -    X is selected from the group consisting of O, S, NR¹⁵, CHOR¹¹, CH₂,     CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and CH₂ and     especially O and S, -    Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl or     pyridinyl, and -    R¹⁰ is selected from the group consisting of H, alkyl comprising 1     to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl Comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,     (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹, (CH₂)_(n)CONR¹¹R¹²,     (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably selected     from the group consisting of alkyl comprising 1 to 4 carbon atoms,     (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³,     (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially     (CH₂)_(n)CONR¹¹R¹², wherein -    n is 0, 1 or 2, preferably 0 or 1 and -    r is 0, 1 or 2, preferably 0 or 1; -   II.13) R⁸ is selected from the group consisting of alkyl comprising     1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     wherein -    n is 0 or 1, -    u is 0 or 2, preferably 0, and -    q is 0 or 1, and -    X is selected from the group consisting of O, S, NR¹⁵, CHOR¹¹, CH₂,     CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and CH₂ and     especially O and S, -    Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl or     pyridinyl, and -    R¹⁰ is selected from the group consisting of H, alkyl comprising 1     to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,     (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹, (CH₂)_(n)CONR¹¹R¹²,     (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably selected     from the group consisting of alkyl comprising 1 to 4 carbon atoms,     (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³,     (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially     (CH₂)_(n)CONR¹¹R¹², wherein -    n is 0, 1 or 2, preferably 0 or 1 and -    r is 0, 1 or 2, preferably 0 or 1; -   II.14) R⁸ is selected from the group consisting of alkyl comprising     1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     wherein -    u is 0 or 2, preferably 0, and -    q is 0 or 1, and -    X is selected from the group consisting of O, S, NR¹⁵, CHOR¹¹, CH₂,     CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and CH₂ and     especially O and S, -    Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl or     pyridinyl, and -    R¹⁰ is selected from the group consisting of H, alkyl comprising 1     to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,     (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹, (CH₂)CONR¹¹R¹²,     (CH₂)_(n)SO₂NR¹¹R¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably selected     from the group consisting of alkyl comprising 1 to 4 carbon atoms,     (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³,     (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially     (CH₂)_(n)CONR¹¹R¹², wherein -    n is 0, 1 or 2, preferably 0 or 1 and -    r is 0, 1 or 2, preferably 0 or 1; -   II.15) R⁸ is selected from the group consisting of alkyl comprising     1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     wherein -    q is 0 or 1, and -    X is selected from the group consisting of O, S, NR¹⁵; CHOR¹¹, CH₂,     CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and CH₂ and     especially O and S, -    Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl or     pyridinyl, and -    R¹⁰ is selected from the group consisting of H, alkyl comprising 1     to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,     (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹, (CH₂)_(n)CONR¹¹R¹²,     (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably selected     from the group consisting of alkyl comprising 1 to 4 carbon atoms,     (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³,     (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially     (CH₂)_(n)CONR¹¹R¹², wherein -    n is 0, 1 or 2, preferably 0 or 1 and -    r is 0, 1 or 2, preferably 0 or 1; -   II.16) q is 0 or 1, and -    X is selected from the group consisting of O, S, NR¹⁵, CHOR¹¹, CH₂,     CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and CH₂ and     especially O and S, -    Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl or     pyridinyl, and -    R¹⁰ is selected from the group consisting of H, alkyl comprising 1     to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,     (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹, (CH₂)_(n)CONR¹¹R¹²,     (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably selected     from the group consisting of alkyl comprising 1 to 4 carbon atoms,     (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³,     (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially     (CH₂)_(n)CONR¹¹R¹², wherein -    n is 0, 1 or 2, preferably 0 or 1 and -    r is 0, 1 or 2, preferably 0 or 1; -   II.17) X is selected from the group consisting of O, S, NR¹⁵,     CHOR¹¹, CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S     and CH₂ and especially O and S, -    Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl or     pyridinyl, and -    R¹⁰ is selected from the group consisting of H, alkyl comprising 1     to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²     (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹, (CH₂)_(n)CONR¹¹R¹²,     (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably selected     from the group consisting of alkyl comprising 1 to 4 carbon atoms,     (CH₂)_(n)NR¹¹R¹² (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³,     (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially     (CH₂)_(n)CONR¹¹R¹², wherein -    n is 0, 1 or 2, preferably 0 or 1 and -    r is 0, 1 or 2, preferably 0 or 1; -   II.18) Ar² is phenyl, pyridinyl or pyrimidyl, and especially is     phenyl or pyridinyl, and -    R¹⁰ is selected from the group consisting of H, ally comprising 1     to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,     CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,     (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,     (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹, (CH₂)_(n)CONR¹¹R¹²,     (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably selected     from the group consisting of alkyl comprising 1 to 4 carbon atoms,     (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³,     (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially     (CH₂)_(n)CONR¹¹R¹², wherein -    n is 0, 1 or 2, preferably 0 or 1 and -    r is 0, 1 or 2, preferably 0 or 1; -   II.19) R¹⁰ is selected from the group consisting of H, alkyl     comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon     atoms, Hal, CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon     atoms, NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹²,     (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     preferably selected from the group consisting of alkyl comprising 1     to 4 carbon atoms, (CH₂)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,     (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹, (CH₂)_(n)CONR¹¹R¹² and especially     (CH₂)_(n)CONR¹¹R¹², wherein -    n is 0, 1 or 2, preferably 0 or 1 and -    r is 0, 1 or 2, preferably 0 or 1; -   II.20) R¹⁰ is selected from the group consisting of H, alkyl     comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon     atoms; Hal, CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon     atoms, NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹²,     (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹,     (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,     preferably selected from the group consisting of alkyl comprising 1     to 4 carbon atoms, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,     (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially     (CH₂)_(n)CONR¹¹R¹², and -    r is 0, 1 or 2, preferably 0 or 1.

One preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein p is 1, 2 or 3 and R⁸ is independently selected from the group consisting of methyl, ethyl, isopropyl, tert.-butyl, F, Cl, Br, CF₃, C(CF₃)₃, methoxy, ethoxy, tert.-butoxy, perfluoro tert.-butoxy (OC(CF₃)₃), methyl sulfanyl (SCH₃), ethyl sulfanyl (SCH₂CH₃), acetyl (COCH₃), propionyl (COCH₂CH₃), butyryl (COCH₂CH₂CH₃). If p is 2 or 3, all substituents can, be the same or different.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein X is selected from the group consisting of S, N—R²¹, CH₂, CH₂CH₂, OCH₂ and CH₂O.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein X is selected from the group consisting of S, CH₂.

Another even more preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein X is O.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein Y is selected from the group consisting of C(R²²)—NO₂, C(R²²)—CN and C(CN)₂.

Another more preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein Y is selected from the group consisting of O, S and NR²¹.

Another even more preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein Y is selected from the group consisting of O and S.

Another even more preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein Y is O.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein Ar² is pyridinyl.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein r is either 0 or 1. If r is 1, R¹⁰ is preferably (CH₂)_(n)CONR¹¹R¹² and especially (CH₂)_(n)CONR¹¹R¹², wherein n in 0. In this embodiment, R¹¹ is preferably selected from the group consisting of H and A and more preferred from H and alkyl, and R¹² is preferably selected from the group consisting of H and A and more preferred from H and alkyl. Especially preferred as residue R¹⁰ are carbamoyl, more preferred alkyl carbamoyl or diaalkyl carbamoyl, even more preferred methyl carbamoyl or dimethyl carbamoyl, ethyl carbamoyl or diethyl carbamoyl and especially preferred methyl carbamoyl (—CONHCH₃). This embodiment is especially preferred when Ar² is pyridinyl. When Ar² is pyridinyl, R¹⁰ is preferably bonded in a vicinal position to the nitrogen atom of the pyrindiyl residue, i.e. in 2- and/or 6-position of the pyridinyl residue.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein r is either 0 or 1. If r is 1, R¹⁰ is preferably (CH₂)_(n)CONR¹¹R¹² and especially (CH₂)_(n)CONR¹¹R¹², wherein n is 0. In this embodiment, R¹¹ is preferably selected from the group consisting of H and A, more preferred from H and alkyl and especially is H, and R¹² is preferably selected from the group consisting of H and A and more preferred from H, unsubstituted alkyl and substituted alkyl, preferably comprising 1 to 6 and especially 1 or 2 carbon atoms. Suitable for substituents include amino groups, such as NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂ and NH(CH₂CH₃), and carboxyl groups and derivatives thereof, such as COOH, COOCH₃, CONH₂, and CONHCH₃. Especially preferred as residue R¹⁰ are CONHCH₃, CONHCH₂CH₂NH₂, CONHCH₂CH₂NHCH₃, CONHCH₂CH₂N(CH₃)₂, CONHCH₂COOH and CONHCH₂CH₂COOH. This embodiment is especially preferred when Ar² is pyridinyl. When Ar² is pyridinyl, R¹⁰ is preferably bonded in a vicinal position to the nitrogen atom of the pyrindiyl residue, i.e. in 2- and/or 6-position of the pyridinyl residue.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein Ar¹ comprises two or more substituents R⁸, wherein one or more, preferably one substituent R⁸ is selected from the group consisting of (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)NR¹¹(CH₂)_(k)OR¹², (CH₂)_(n)NPR¹¹(CH₂)_(k)NR¹²R¹², (CH₂)_(n)COOR¹¹ and (CH₂)_(n)S(O)_(u)R¹³ wherein R¹¹, R¹² and R¹³ are defined as above and n is as defined above, preferably n is 0, 1 or 2 and especially is 0, k is 1 to 4 and preferably 1 or 2, and u is preferably 2. In this embodiment R¹¹, R¹² and R¹³ are more preferably selected independently from each other from the group consisting of H, methyl and ethyl. In this embodiment, one or two substituents R⁸ and preferably one substituent R₈ is especially preferably selected from the group consisting of NH₂, N(CH₃)₂, N(C₂H₅)₂, NHCH₂CH₂NH₂, N(CH₃)CH₂CH₂NH₂, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂OCH₃, OCH₂CH₂N(CH₃)₂, SCH₃, SC₂H₅, SO₂CH₃, COOCH₃ and COOH. Accordingly, in this embodiment Ar¹ especially preferably comprises at least one substituent R⁸ other than (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)NR¹¹(CH₂)_(k)OR¹², (CH₂)_(n)NR¹¹(CH₂)_(k)NR¹²R¹², (CH₂)_(n)COOR¹³ and (CH₂)_(n)S(O)_(u)R¹³ as defined in this paragraph and especially other than NH₂, N(CH₃)₂, N(C₂H₅)₂, NHCH₂CH₂NH₂, N(CH₃)CH₂CH₂NH₂, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂OCH₃, OCH₂CH₂N(CH₃)₂, SCH₃, SC₂H₅, SO₂CH₃, COOCH₃ and COOH.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein q is 1, i.e. the phenylen moiety bound to the glycine amide group and the radical X is substituted once, preferably by a substituent selected from the group consisting of alkyl and halogen and more preferred from methyl, ethyl, F, Cl and Br.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1). to II.20), wherein q is 0, i.e. the phenylen moiety bound to the glycine amide group and the radical X is unsubstituted.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of formulae II.1) to II.20), wherein (R⁸)_(p)—Ar¹ is selected from the group consisting of 3-acetyl-phenyl, 4-acetyl-phenyl, 2-bromo-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 4-bromo-2-chloro-phenyl, 4-bromo-3-methyl-phenyl, 4-bromo-3-trifluoromethyl-phenyl, 2-chloro-phenyl, 2-chloro-4-trifluoromethyl-phenyl, 2-chloro-5-trifluoromethyl-phenyl, 3-chloro-phenyl, 3-chloro-4-methyl-phenyl, 3-chloro-4-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 4-chloro-phenyl, 4-chloro-2-trifluoromethyl-phenyl, 4-chloro-3-trifluoromethyl-phenyl, 4-chloro-2-methyl-phenyl, 5-chloro-2-methyl-phenyl, 5-chloro-2-methoxy-phenyl, 4-chloro-2-methoxy-5-methyl-phenyl, 4-chloro-2-methoxy-5-trifluoromethyl-phenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 3,4-dichloro-phenyl, 3,5-dichloro-phenyl, 2,4,5-trichloro-phenyl, 4-fluoro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 4-ethoxy-phenyl, 2-methoxy-phenyl, 2-methoxy-5-trifluoromethylphenyl, 4-methoxy-phenyl, 2,5-dimethoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 3-trifluoromethoxy-phenyl, 4-trifluoromethyl-phenyl, 4-trifluoromethoxy-phenyl, 3,5-bis-trifluoromethyl-phenyl, 3-methoxy-phenyl, 3-methylsulfanyl-phenyl, 4-methylsulfanyl-phenyl, o-tolyl (2-methyl-phenyl), m-tolyl (3-methyl-phenyl), p-tolyl (4-methyl-phenyl), 2,3-dimethyl-phenyl, 2,3-di-methyl-phenyl, 2,5-dimethyl-phenyl, 3,4-dimethyl-phenyl, 3,5-dimethyl-phenyl, 2-ethyl-phenyl, 3-ethyl-phenyl, 4-ethyl-phenyl, 4-isopropyl-phenyl, 4-tert-butyl-phenyl and 5-tert-butyl-isoxazol-3-yl.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein (R⁸)_(p)—Ar¹ is as defined above, but comprises one or more additional residues, preferably one additional residue. The additional residues are preferably selected from the meanings given for R⁸ and more preferably selected from the group consisting of (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)NR¹¹(CH₂)_(k)OR¹², (CH₂)_(n)NR¹¹(CH₂)_(k)NR¹²R¹², (CH₂)_(n)COOR¹³ and (CH₂)_(n)S(O)_(u)R¹³ wherein R¹¹, R¹² and R¹³ are defined as above and n is as defined above, preferably n is 0, 1 or 2 and especially is 0, k is 1 to 4 and preferably 1 or 2, and u is preferably 2. In this embodiment R¹¹, R¹² and R¹³ are more preferably selected independently from each other from the group consisting of H, methyl and ethyl. Even more preferred, the additional residue(s) is/are selected from the group consisting of NH₂, N(CH₃)₂, N(C₂H₅)₂, NHCH₂CH₂NH₂, N(CH₃)CH₂CH₂NH₂, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂OCH₃, OCH₂CH₂N(CH₃)₂, SCH₃, SC₂H₅, SO₂CH₃, COOCH₃ and COOH.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein X is bonded in the para- (p-) or metha- (m-) position to the phenyl residue that is bonded directly to the glycine amide moiety.

Another preferred embodiment of the instant invention relates to compounds of formula 31 and preferably one or more of sub formulae II.1) to II.20), wherein Ar² is a pyridinyl residue and wherein said pyridinyl residue is bonded to X in the 3- or 4-position, preferably the 4-position, relative to the nitrogen atom of the pyridinyl residue.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein Ar² comprises one or more substituents R¹⁰ and wherein one or two, preferably one substituent R¹⁰ is selected from unsubstituted or substituted carbamoyl moieties. Substituted carbamoyl moieties are preferably selected from CONHR²³ or CONR²³R²⁴, preferably CONHR²³, wherein R²³ and R²⁴ are independently selected from the definitions given for R⁸, more preferably selected from alkyl, preferably methyl, ethyl, propyl and butyl, (CH₂)_(n)NR¹¹R¹² and (CH₂)_(n)OR¹², wherein R¹¹, R¹² and n are as defined above. In this embodiment, n is preferably not 0 and more preferred 1 to 3 and especially 1 or 2. Preferred examples for R²³ are selected from the group consisting of methyl, ethyl, CH₂CH₂NH₂, CH₂CH₂N(C₃)₂, CH₂CH₂N(CH₂CH₃)₂, CH₂CH₂OH, CH₂CH₂OCH₃ and CH₂CH₂OCH₂CH₃.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein Ar² comprises one or more substituents R¹⁰ and wherein one or two, preferably one substituent R¹⁰ is selected from substituted carbamoyl moieties. Substituted carbamoyl moieties are preferably selected from CONHR²³, wherein R²³ is preferably unsubstituted C₁-C₄ alkyl and especially methyl.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein Ar² comprises one or more substituents R¹⁰ and wherein one or two, preferably one substituent R¹⁰ is selected from substituted carbamoyl moieties. Substituted carbamoyl moieties are preferably selected from CONHR²³ wherein R²³ selected from (CH₂)_(n)NR¹¹R¹² and (CH₂)_(n)OR¹², wherein R¹¹, R¹² and n are as defined above. In this embodiment, n is preferably not 0 and more preferred 1 to 3 and especially 1 or 2. Preferred examples for R²³ are selected from the group consisting of CH₂CH₂NH₂, CH₂CH₂N(CH₃)₂, CH₂CH₂N(CH₂CH₃)₂, CH₂CH₂OH, CH₂CH₂OCH₃ and CH₂CH₂OCH₂CH₃.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein Ar¹ comprises one or more substituents R⁸ and wherein one or two, preferably one substituent R⁸ is selected from the group consisting of NH₂, N(CH₃)₂, NHCH₃, N(C₂H₅)₂, HNCH₂CH₂NH₂, OCH₂CH₂NH₂, HOCH₂CH₂NH, OCH₂CH₂NHCH₃, N(CH₃)CH₂CH₂NH₂, HN(CH₃)CH₂CH₂NH, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂OCH₃, OCH₂CH₂N(CH₃)₂, OCH₂CH₂N(CH₂CH₃)₂, SCH₃, SC₂H₅, and compounds of the formulae

and/or Ar² comprises one or more substituents R¹⁰ and wherein one or two, preferably one substituent R¹⁰ is independently selected from the meanings given for R⁸ in this paragraph.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein —Ar²—(R¹⁰)_(r) is selected from the formulae

wherein R¹⁰, R²³ and R²⁴ are as defined above and below.

Another especially preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20), wherein one or more features of the above and below mentioned embodiments are combined in one compound.

Subject of the present invention are therefore especially preferred compounds of formula II according to one or more of the formulae IIa, IIb, IIc, IId, IIe IIf, IIg and IIh,

Wherein R⁸, p, Y, R⁹ and q are as defined above and below, R¹⁰ is H or as defined above/below, and preferably as defined in sub formulae II.1) to II.20) and/or the embodiments related thereto.

Another preferred embodiment of the instant invention relates to compounds of formula II and preferably one or more of sub formulae II.1) to II.20) and IIa to IIh, wherein R¹⁰ is H or a substituted carbamoyl moiety CONHR²³ or CONR²³R²⁴, preferably CONHR²³, wherein R²³ and R²⁴ are independently selected from the definitions given for R⁸, more preferably selected from (CH₂)_(n)NR¹¹R¹² and (CH₂)_(n)OR¹², wherein R¹¹, R¹² and n are as defined above. In this embodiment, n is preferably not 0 and more preferred 1 to 3 and especially 1 or 2. Preferred examples for R²³ are selected from the group consisting of CH₂CH₂NH₂, CH₂CH₂N(CH₃)₂, CH₂CH₂N(CH₂CH₃)₂, CH₂CH₂OH, CH₂CH₂OCH₃ and CH₂CH₂OCH₂CH₃.

It is understood that when a residue, for example R⁸, R⁹, R¹⁰ or R¹⁴ or R²³, is comprised twice or more times in one or more of the formulae I, II and the sub formulae corresponding thereto, it is in each case independently from one another selected from the meanings given for the respective residue. For example, R¹¹ and R¹² are defined to be independently selected from a group consisting of H, A, (CH₂)_(m)Ar³ and (CH₂)_(m)Het. Then (CH₂9_(n)NR¹¹(CH₂)_(m)NR¹²R¹² can be (CH₂)_(n)NA(CH₂)_(m)NA₂ (if R¹¹=A, R¹²=A and R¹²=H) as well as (CH₂)_(n)NA(CH₂)_(m)NHA (if R¹¹=A, R¹²=H and R¹²=A or (CH₂)_(n)NA(CH₂)_(m)NH(CH_(2m)Het (if R¹¹=A, R¹²=H and R¹²=(CH₂)_(m)Het). Accordingly, if a compound of formula II comprises one residue R8H, R9H and R¹⁰, then for example R⁸, R⁹ and R¹⁰ can all be (CH₂)_(n)COOR¹3⁴, wherein all residues R¹³ are the same (for example CH₂Hal, wherein Hal is Cl; then all residues R⁸, R⁹ and R¹⁰ are the same) or different (for example CH₂Hal, wherein in R⁸ Hal is cl; in R⁹ Hal is F; and in R¹⁰ Hal is Br; then all residues R⁸, R⁹ and R¹⁰ are different); or for example R⁸ is (CH₂)_(n)COOR¹³, R⁹ is NO₂ and R¹⁰ is (CH₂)_(n)SR¹¹, wherein R¹¹ and R¹³ can be the same (for example both can be H or both can be A which is methyl) of different (for example R¹¹ can be H and R¹³ can be A which is methyl).

If not stated otherwise, reference to compounds of formula I and formula II also includes the sub formulae related thereto, especially sub formulae II.1) to II.20) and IIa to IIh.

Subject of the instant invention are especially those compounds of formula I and/or formula II, in which at least one of the residues mentioned in said formulae has one of the preferred or especially preferred meanings given above and below.

The present invention further relates to compounds (1) to (8) as given below:

(1): N-(4-Chloro-3-trifluoromethyl-phenyl)-2-[4-(pyridin-4-yloxy)-phenylamino]-acetamide

(2): N-(4-Chloro-5-trifluoromethyl-phenyl)-2-[3-(pyridin-4-yloxy)-phenylamino]-acetamide

(3): N-(4-Chloro-3-trifluoromethyl-phenyl)-2-[4-(pyridin-3-yloxy)-phenylamino]-acetamide

(4): N-(4-Chloro-3-trifluoromethyl-phenyl)-2-[3-(pyridin-3-yloxy)-phenylamino]-acetamide

(5): N-(3-tert.-Butyl-isoxazol-5-yl)-2-[3-(pyridin-4-yloxy)-phenylamino]-acetamide

(6): N-(3-tert.-Butyl-isoxazol-5-yl)-2-[4-(pyridin-4-yloxy)-phenylamino]-acetamide

(7): N-(5-tert.Butyl-isoxazol-3-yl)-2-[3-(pyridin-4-yloxy)-phenylamino]-acetamide

(8): N-(5-tert.-Butyl-isoxazol-3-yl)-2-[4-(pyridin-4-yloxy)-phenylamino]-acetamide

-   The present invention also relates to compounds (9) to (235) of     formula A-NH—CO—CH₂—NH—B, wherein A and B are as given in the table     below:

A B  (9)

 (10)

 (11)

 (12)

 (13)

 (14)

 (15)

 (16)

 (17)

 (18)

 (19)

 (20)

 (21)

 (22)

 (23)

 (24)

 (25)

 (26)

 (27)

 (28)

 (29)

 (30)

 (31)

 (32)

 (33)

 (34)

 (35)

 (36)

 (37)

 (38)

 (39)

 (40)

 (41)

 (42)

 (43)

 (44)

 (45)

 (46)

 (47)

 (48)

 (49)

 (50)

 (51)

 (52)

 (53)

 (54)

 (55)

 (56)

 (57)

 (58)

 (59)

 (60)

 (61)

 (62)

 (63)

 (64)

 (65)

 (66)

 (67)

 (68)

 (69)

 (70)

 (71)

 (72)

 (73)

 (74)

 (75)

 (76)

 (77)

 (78)

 (79)

 (80)

 (81)

 (82)

 (83)

 (84)

 (85)

 (86)

 (87)

 (88)

 (89)

 (90)

 (91)

 (92)

 (93)

 (94)

 (95)

 (96)

 (97)

 (98)

 (99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

(107)

(108)

(109)

(110)

(111)

(112)

(113)

(114)

(115)

(116)

(117)

(118)

(119)

(120)

(121)

(122)

(123)

(124)

(125)

(126)

(127)

(128)

(129)

(130)

(131)

(132)

(133)

(134)

(135)

(136)

(137)

(138)

(139)

(140)

(141)

(142)

(143)

(144)

(145)

(146)

(147)

(148)

(149)

(150)

(151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)

(201)

(202)

(203)

(204)

(205)

(206)

(207)

(208)

(209)

(210)

(211)

(212)

(213)

(214)

(215)

(216)

(217)

(218)

(219)

(220)

(221)

(222)

(223)

(224)

(225)

(226)

(227)

(228)

(229)

(230)

(231)

(232)

(233)

(234)

(235)

In a special embodiment, the glycinamide derivatives according to sub formulae IIa, IIb, IIc, IId, IIe, IIg, IIh and/or compounds (1) to (235) additionally comprise one or two substituents selected from the group consisting of O(CH₂)_(n)NR¹¹R¹², NR¹¹(CH₂)_(n)NR¹¹R¹², O(CH₂)_(n)OR¹² and NR¹¹(CH₂)_(n)OR¹²,

wherein

-   R¹¹, R¹² are independently selected from a group consisting of H, A,     (CH₂)_(m)Ar³ and (CH₂)_(m)Het, or in NR¹¹R¹², -   R¹¹ and R¹² form, together with the N-Atom they are bound to, a 5-,     6- or 7-membered heterocyclus which optionally contains 1 or 2     additional hetero atoms, selected from N, O an S, and -   n is 1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4.

In this embodiment, the substituents are preferably selected from the group consisting of HNCH₂CH₂NH₂, OCH₂CH₂NH₂, NHCH₂CH₂OH, OCH₂CH₂NHCH₃, N(CH₃)CH₂CH₂NH₂, HN(CH₃)CH₂CH₂NH, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂OCH₃, OCH₂CH₂N(CH₃)₂, OCH₂CH₂N(CH₂CH₃)₂ and compounds of the formulae

In this embodiment, the additional substituents are preferably bound to one of the aromatic residues directly bound to the glycinamide moiety and/or the pyridinyl residue. Preferably, one additional substituent is bound to the aromatic residue directly bound to the amide-nitrogen atom of the glycinamide moiety and/or one additional substituent is bound to the pyridinyl residue.

The nomenclature as used herein for defining compounds, especially the compounds according to the invention, is in general based on the rules of the IUPAC-organisation for chemical compounds and especially organic compounds.

Another aspect of the invention relates to a method for producing compounds of formula II, characterised in that

-   a) A compound of formula III

-    wherein     -   L¹ is Cl, Br, I, OH, a reactive esterified OH-group or a         diazonium moiety, and R⁸, p, Ar¹, Y are as defined above and         below, -    is reacted -   b) with a compound of formula IV,

-    wherein     -   L², L³ are independently from one another H or a metal ion, and         R⁹, q, X, Ar², R¹⁰ and r are as defined above and below, -    and optionally -   c) isolating and/or treating the compound of formula II obtained by     said reaction with an acid, to obtain the salt thereof.

The compounds of the formula I and preferably the compounds of the formula II and also the starting materials for their preparation are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.

If desired, the starting materials can also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the formula I or II, respectively. On the other hand, it is possible to carry out the reaction stepwise.

The compounds of the formula I and especially the compounds of formula II can preferably be obtained by reacting compounds of the formula III with compounds of the formula IV.

In detail, the reaction of the compounds of the formula III with the compounds of the formula IV is carried out in the presence or absence of a preferably inert solvent at temperatures between about −20° and about 200°, preferably between 0° and 150° and especially between room temperature (25°) and 120°. In many cases, it is advantageous to combine one compound of formula III with one compound of formula IV at the lower end of the given temperature range, preferably between −20° and 75°, more preferred between 0° and 60° and especially between 10° and 40°, for example at about room temperature, and heat the mixture up to a temperature at the upper end of the given temperature range, preferably between 80° and 180°, more preferred between 90° and 150° and especially between 95° and 120°, for example at about 100° or at about 110°.

In general, the compounds of formula III and/or formula IV are new. In any case, they can be prepared according to methods known in the art or analogous to those procedures.

In the compounds of formula III, L¹ is preferably Cl, Br, I, OH, a reactive derivatized OH-moiety, especially a reactive esterified OH-moiety, for example an alkylsulfonyloxy-moiety comprising 1 to 6 carbon atoms (preferably methylsulfonyloxy) or and arylsulfonyloxy-moiety comprising 6 to 10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or diazonium moiety, more preferred Cl, Br or I and even more preferred Cl.

In the compounds of formula IV, L² and/or L³ is preferably H or a moiety which activates the amino group it is bonded to, for example a metal ion. Suitable metal ions are preferably selected from the group consisting of alkaline metal ions, alkaline-earth metal ions and aluminium ions. Especially preferred metal ions are alkaline metal ions, of which Li, Na and K are especially preferred. In case of multi-valent metal ions, the metal ions and the compounds of formula IV form a complex containing one or more compounds of formula IV and one or more metal ions wherein the ratio between compounds of formula IV and metal ions is depending on the valency of the metal ion(s) according to the rules of stoichiometry and/or electroneutrality.

The reaction between the compounds of formula III and compounds of formula IV is preferably carried out in the presence of an acid binding means, for example one or more bases. Suitable acid binding means are known in the art. Preferred as acid binding means are inorganic bases and especially organic bases. Examples for inorganic bases are alkaline or alkaline-earth hydroxides, alkaline or alkaline-earth carbonates and alkaline or alkaline-earth bicarbonates or other salts of a weak acid and alkaline or alkaline-earth metals, preferably of potassium, sodium, calcium or cesium. Examples for organic bases are triethyl amine, diisopropyl ethyl amine (DIPEA), dimethyl aniline, pyridine or chinoline. If an organic base is used, it is advantageous in general to use a base with a boiling point that is higher than the highest reaction temperature employed during the reaction. Especially preferred as organic base is diisopropyl ethyl amine. Reaction times are generally in the range between some minutes and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range 10 min and 24 hrs, preferably 30 min and 12 hrs and especially between 45 min and 8 hrs, for example about 1 h, about 2 hrs, about 4 hrs or about 6 hrs.

Preferably, the reaction of the compounds of the formula III with the compounds of the formula IV is carried out in the presence of a suitable solvent, that is preferably inert under the respective reaction conditions. Examples of suitable solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents. Polar solvents are in general preferred. Examples for suitable polar solvents are chlorinated hydrocarbons, alcohols, glycol ethers, nitrites, amides and sulfoxides or mixtures thereof. More preferred are amides, especially dimethylformamide (DMF).

The compounds of formula III can be obtained according to methods known in the art. In an advantageous manner, they can be readily obtained by reacting a compound of formula V

wherein R⁸, p, and Ar¹ are as defined above/below and L⁴ and L⁵ are selected independently from each other from the meanings given for L² and L³ and more preferred are hydrogen, with a compound of formula VI

wherein Y is as defined above/below and L⁶ and L⁷ are selected independently from each other from the meanings given for L¹. Preferably, L⁶ and/or L⁷ are halogen. More preferred, both L⁶ and L⁷ are independently selected from the group consisting of Cl, Br and I. Especially preferred, both L⁶ and L⁷ are Cl.

Some of the starting materials of the formula V and/or the formula VI are known and preferably commercially available. If they are not known, they can be prepared by methods known per se.

Suitable reaction conditions for carrying out reaction of compounds of formula V with compounds of formula VI are known in the art. In detail, the reaction of the compounds of the formula V with the compounds of the formula VI is carried out in the presence or absence of a preferably inert solvent at temperatures between about −40° and about 180°, preferably between −20° C. and 100° and especially between −10° and 50°, for example at about 0° and/or about room temperature (25°). In many cases, it is advantageous to combine one compound of formula V with one compound of formula VI at the lower end of the given temperature range, preferably between −20° and 40°, more preferred between −10° and 20° and especially between −5° and 10°, for example at about 0°, and heat the mixture up to a temperature at the upper end of the given temperature range, preferably between 20° and 150°, more preferred between 20° and 100° and especially between 20° and 50°, for example at about room temperature.

The reaction between compounds of formula V and compounds of formula VI is preferably carried out in the presence of an acid binding means, for example one or more bases. Suitable acid binding means are known in the art. Preferred as acid binding means are inorganic bases and especially organic bases. Examples for inorganic bases are alkaline or alkaline-earth hydroxides, alkaline or alkaline-earth carbonates and alkaline or alkaline-earth bicarbonates or other salts of a weak acid and alkaline or alkaline-earth metals, preferably of potassium, sodium, calcium or cesium. Examples for organic bases are triethyl amine, diisopropyl ethyl amine (DIPEA), dimethyl aniline, pyridine or chinoline. If an organic base is used, it is advantageous in general to use a base with a boiling point that is higher than the highest reaction temperature employed during the reaction. Especially preferred as organic base is pyridine.

The reaction between compounds of formula V and compounds of formula VI can be carried out in the presence of a suitable solvent, that is preferably inert at the chosen reaction conditions. Suitable solvents are known in the art. Examples of suitable solvents include hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; nitriles, such as acetonitrile; esters, such as ethyl acetate, or mixtures of the aid solvents. Non-protic solvents are in general preferred.

If the reaction between a compound of formula V and a compound of formula VI is carried out in presence of an organic base that is liquid at the chosen reaction conditions, preferably no additional solvent is used.

The compounds of formula IV can be obtained according to methods known in the art.

If the compound of formula IV is a compound according to formula IVa,

it can be readily obtained in an advantageous manner by reacting a compound of formula VIIa,

wherein R⁹ and q are as defined above/below, with a compound of formula VIII,

L⁸-X-Ar²(R¹⁰)_(r)  VIII

wherein L⁸ is H or a metal ion, preferably a metal ion selected from the group consisting of alkaline metal ions, alkaline-earth metal ions and aluminum ions, especially preferred alkaline metal ions, of which Li, Na and K are especially preferred, and even more preferred is H; and Ar², R¹⁰, r and X are as defined above/below, and especially wherein X is (CHR¹¹)_(h)-Q-(CHR¹²)_(i), wherein R¹¹, h and R¹² are defined above/below, j is 0 and Q is selected from a group consisting of O, S, N—R¹⁵, (CHR¹⁸—O)_(j), (CHR¹⁸CHR¹⁹—O)_(j), CH═N—O, CH═N—NR¹⁵, SO₂NR¹⁵, wherein R¹⁵, R¹⁸ and R¹⁹ are as defined above/below; optionally isolating the reaction product, and transferring the obtained reaction product of formula IX

into a compound of formula IVa, preferably by hydrogenating the NO₂-moiety of the compound of formula IX into a NH₂-moiety. Methods and reaction conditions for hydrogenating said NO₂-moiety into a NH₂-moiety are known in the art. In general, it is advantageous to carry out the hydrogenation reaction in a hydrogen atmosphere in the presence of a suitable catalyst, preferably a Palladium catalyst, for example Pd/C. In general, such hydrogenation reactions are carried out in a suitable solvent. Suitable solvents for hydrogenation reactions are known in the art. Suitable solvents, for example, are alcohols, especially methanol and ethanol and ethers, especially THF, and mixtures thereof. In general, the hydrogenation reactions are carried out at about normal pressure or slightly elevated pressure, for example between normal pressure and 3 bar pressure (about 300 kPa). The hydrogenation reaction is usually carried out in the temperature range between −20° and 150°, preferably 0° and 50°.

Ar² is preferably pyridinyl. Accordingly, the compound of formula VIII is preferably selected from the group consisting of formulae VIIIa and VIIIb,

wherein L⁸, X, R¹⁰ and r are as defined above, and especially preferred from the group consisting of formulae VIIIc and VIIId,

wherein R¹⁰ and r are as defined above, or the alkaline metal salts and especially the sodium or potassium salts thereof.

Accordingly, in formulae IVa, VIIII, VIIIa, VIIIb and IX, the bridging group X is preferably O, S, OCH₂ and OCH₂CH₂ and especially is O.

In the formulae VIII, VIIIa and VIIIb, L⁸ is preferably H or selected from the group consisting of Na, K and Cs and especially preferred is H.

In general, this reaction is advantageous to produce compounds of formula IVaa,

wherein R⁹, q, X, Ar², R¹⁰ and r are as defined above/below.

To obtain compounds of formula IVaa, it is reasonable to employ a compound of formula VII that is selected from the compounds of formula VIIa,

and proceed the reaction as described above/below.

Accordingly, by starting from a compound of formula VIIIa and a compound of formula VIIIa, the reaction preferably leads to compounds of formula IVaaa,

wherein R⁹, q, X, R¹⁰ and r are as defined above/below.

Accordingly, by starting from a compound of formula VIIIa and a compound of formula VIIIb, the reaction preferably leads to compounds of formula IVaab,

wherein R⁹, q, X, R¹⁰ and r are as defined above/below.

Accordingly, by starting from a compound of formula VIIIa and a compound of formula VIIIc, the reaction preferably leads to compounds of formula IVaac,

wherein R⁹, q, R¹⁰ and r are as defined above/below.

Accordingly, by starting from a compound of formula VIIa and a compound of formula VIIId, the reaction preferably leads to compounds of formula

wherein R⁹, q, R¹⁰ and r are as defined above/below.

Some of the starting materials of the formula VIII and/or the formula VIII are known and preferably commercially available. If they are not known, they can be prepared by methods known per se.

The reaction between the compound of formula VII and VIII is preferably carried out in the temperature range between 0° and 250°, more preferred room temperature and 200°, for example at about 120°, at about 150° or at about 180°. Reaction times depend on the respective reactants and the respective reaction temperature, but generally lie in the range between 30 min and 36 hrs, preferably 3 hrs and 24 hrs, more preferably 8 hrs and 20 hrs for example about 10 hrs, about 16 hrs or about 18 hrs.

The reaction can be carried out in the absence of solvent or preferably in the presence of an solvent, preferable a solvent that is inert under the respective reaction conditions. Suitable inert solvents for carrying out the reaction are known in the art. Examples for suitable solvents are high boiling aliphatic hydrocarbons, high boiling aromatic carbons, for example toluene, xylenes, high boiling chlorinated hydrocarbons, such as trichloroethylene, tetrachloroethanes, pentachlo roethanes and hexachloroethanes; high boiling ethers, such as ethylene glycol and propylene glycols; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methyl pyrrolidinone (NMP); sulfoxides, such as dimethyl sulfoxide (DMSO); or mixtures of the said solvents. Preferred are amides, especially dimethylformamide (DMF).

Preferably, the reaction is carried out in the presence of a base. Suitable bases are known in the art. Preferred bases are organic bases and especially inorganic bases. Examples for inorganic bases are alkaline or alkaline-earth hydroxides, alkaline or alkaline-earth carbonates and alkaline or alkaline-earth bicarbonates or other salts of a weak acid and alkaline or alkaline-earth metals, preferably of potassium, sodium, calcium or cesium. Preferred inorganic bases are K₂CO₃, Na₂CO₃, MgCO₃, CaCO₃, NaOH and KOH, especially preferred is K₂CO₃. Examples for organic bases are triethyl amine, diisopropyl ethyl amine (DIPEA), dimethyl aniline, pyridine or chinoline. If an organic base is used, it is advantageous in general to use a base with a boiling point that is higher than the highest reaction temperature employed during the reaction.

Alternatively, if the compound of formula IV is a compound according to formula IVb,

it can be readily obtained in an advantageous manner by reacting a compound of formula VIIIb,

wherein R⁹ and q are as defined above/below and wherein L⁹ is selected independently from the meanings given for L¹. Preferably, L⁹ is halogen. More preferred, L⁹ is selected from the group consisting of Cl, Br and I. Especially preferred, L⁹ is Cl. with a compound of formula VIIIb,

L¹⁰-X—Ar²(R¹⁰)_(r)  VIIIb

wherein L¹⁰ is H or a metal ion, preferably a metal ion, more preferred a metal ion selected from the group consisting of alkaline metal ions, alkaline-earth metal ions and aluminium ions, especially preferred alkaline metal ions, of which Li, Na and K are especially preferred; and Ar², R¹⁰, r and X are as defined above/below, and especially wherein X is (CHR¹¹)_(h)-Q-(CHR¹²)_(i), CH═N—O, CH═N—NR¹⁵, SO₂NR¹⁵, wherein R¹⁵, R¹⁸ and R¹⁹ are as defined above/below; optionally isolating the reaction product, and transferring the obtained reaction product of formula IXb

into a compound of formula Iva, preferably by hydrogenating the NO_(2″) -moiety of the compound of formula IX into a NH₂-moiety. Methods and reaction conditions for hydrogenating said NO₂-moiety into a NH₂-moiety are known in the art. In general, it is advantageous to carry out the hydrogenation reaction in a hydrogen atmosphere in the presence of a suitable catalyst, preferably a Palladium catalyst, for example Pd/C. in general, such hydrogenation reactions are carried out in a suitable solvent. Suitable solvents for hydrogenation reactions are carried out in a suitable solvent. Suitable solvents for hydrogenation reactions are known in the art. Suitable solvents, for example, are alcohols, especially methanol and ethanol, ethers, especially THF, and mixtures thereof. In general, the hydrogenation reactions are carried out at about normal pressure or slightly elevated pressure, for example between normal pressure or slightly elevated pressure, for example between normal pressure and 3 bar pressure (about 300 kPa). The hydrogenation reaction is usually carried out in the temperature range between −20° and 150°, preferably 0° and 50°.

Ar² is preferably pyridinyl. Accordingly, the compound of formula VIIIb is preferably selected from the group consisting of formulae VIIIe and VIIIf,

wherein L¹⁰, X, R¹⁰ and r are as defined above, and especially preferred from the group consisting of formulae VIIIg and VIIIh,

wherein R¹⁰ and r are as defined above, and wherein M is an alkaline metal ion and especially sodium or potassium, or the corresponding alcohols thereof.

Accordingly, in formulae IVb, VIIIb, VIIIe, VIIIf and IXb, the bridging group X is preferably O, S, OCH₂ and OCH₂CH₂ and especially is O.

In general, this alternative reaction is advantageous to produce compounds of formula IVbb,

wherein R⁹, q, X, Ar², R¹⁰ and r are as defined above/below.

To obtain compounds of formula IVbb, it is reasonable to employ a compound of formula VIIb that is selected from the compounds of formula VIIbb,

wherein hal is as defined above/below and especially is Cl, and proceed the alternative reaction as described above/below.

Accordingly, by starting from a compound a formula VIIbb and a compound of formula VIIe, the reaction preferably leads to compounds of formula IVbbe,

wherein R⁹, q, X, R¹⁰ and r are as defined above/below.

Accordingly, by starting from a compound of formula VIIbb and a compound of formula VIIIf, the reaction preferably leads to compounds of formula IVbbf,

wherein R⁹, q, X, R¹⁰ and rare as defined above/below.

Accordingly, by starting from a compound of formula VIIbb and a compound of formula VIIIg, the reaction preferably leads to compounds of formula IVbbg,

wherein R⁹, q, R¹⁰ and r are as defined above/below.

Accordingly, by starting from a compound of formula VIIb and a compound of formula VIIIh, the reaction preferably leads to compounds of formula IVbbh,

wherein R⁹, q, R¹⁰ and r are as defined above/below.

Some of the starting materials of the formula VIIIb and/or the formula VIIIb are known and preferably commercially available. If they are not known, they can be prepared by methods known per se.

The reaction between the compound of formula VIIIb and VIIIb is preferably carried out in the temperature range between 0° and 25°, more preferred 50° and 220°, for example at about 90°, at about 120°, at about 160°, at about 180° or at about 200°. Reaction times depend on the respective reactants and the respective reaction temperature, but generally lie in the range between 10 min and 24 hrs, preferably 30 min and 12 hrs, more preferably 1 h and 6 hrs for example about 1.5 hrs, about 3 hrs, about 4 hrs or about 5 hrs.

The reaction can be carried out in the absence or the presence of a solvent, preferable a solvent that is inert under the respective reaction conditions. Suitable inert solvents for carrying out the reaction are known in the art. Examples for suitable solvents are high aliphatic hydrocarbons, aromatic carbons, for example toluene and xylenes, high boiling chlorinated hydrocarbons, such as dichloromethane, trichloromethane trichloroethylene, tetrachloroethanes, pentachloroethanes and hexachloroethanes; ethers, such as diethylether, tert.-butyl methyl ether, ethylene glycol and propylene glycols; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl, ether (diglyme); nitriles, such as acetonitrile, amides such as acetamide, diemthyacetamide, dimethyltormamide (DMF) or N-methylpyrrolidinone (NMP); sulfoxides, such as dimethyl sulfoxide (DMSO); or mixtures of the said solvents.

Preferably, the reaction is carried out in the presence of a catalyst. Suitable catalysts are known in the art. Preferred catalytic active metals and especially copper.

Preferably, the reaction is carried out by heating up a reaction mixture comprising one compound of formula VIIIb and one compound of formula VIIIb to a suitable reaction temperature, which preferably lies at the upper end of the given temperature ranges and more preferred is in the range between 150° and 200°, for example at about 180°, preferably in the presence of the suitable catalyst and especially in the presence of copper. Reaction times at this temperature are preferably as given above and especially in the range between 1 h and 5 hrs, for example about 3 hrs. Preferably, the reaction mixture is then allowed to cool down to a temperature in the lower range of the given temperature, more preferred to a temperature in the range between 50° and 150°, for example to about 90°. Preferably, a suitable solvent, especially tert.-butyl methyl ether, is then added and the reaction mixture is preferably kept at about the same temperature for some more time, preferably for 30 min to 2 hrs and more preferred for about one hour.

If the compound IV is a compound according to formula IVc,

it can be readily obtained in an advantageous manner by reacting a compound of formula XI

wherein L⁹ is H or a metal ion, preferably a metal ion selected from the group consisting of alkaline metal ions, alkaline-earth metal ions and aluminium ions, especially preferred alkaline metal ions, of which Li, Na and K are especially preferred, and even more preferred is H; and R⁹, q and X are as defined above/below, and especially wherein X is (CHR¹¹)_(h)-Q-(CHR¹²)_(l), wherein R¹¹, h and R¹² are defined above/below, j is 0 and Q is selected from a group consisting of O, S, N—R¹⁵, (CHR¹⁸—O)_(j), (CHR¹⁸CHR¹⁹—O)_(j), CH═N—O, CH═N—NR¹⁵, SO₂NR¹⁵, wherein R¹⁵, R¹⁸ and R¹⁹ are as defined above/below; with a compound of formula XII,

wherein hal is independently select selected from the group consisting of Cl, Br and I, the residue R¹⁰ are the same or different and have the meanings given above/below and preferably have both the same meaning, and the indices r are the same or different and have the meanings given above/below and preferably are the same, optionally isolating the reaction product, and transferring the obtained reaction product of formula XIII

into a compound of formula IVc, preferably by hydrogenating the NO₂-moiety of the compound of formula XIII into a NH₂-moiety, for example as described above for the compound of formula IX.

In the compounds IVc, XII and XIII, r is preferably in each case identical and even more preferred in each case 0.

In formulae IVc, XI and XIII, the bridging group X is preferably O, S, OCH₂ and OCH₂CH₂ and especially is O.

In the formula XI, L⁹ is preferably H or selected from the group consisting of Na and K and especially preferred is H.

The reaction between the compound of formula XI and XII is preferably carried out in the temperature range between 0° and 250°, more preferred room temperature and 200°, for example at about 120°, at about 150° or at about 180°. Reaction times depend on the respective reactants and the respective reaction temperature, but generally lie in the range between 30 min and 24 hrs, preferably one hour and 12 hrs, for example about 2 hrs, about 3 hrs or about 6 hrs. The reaction can be carried out in the absence of solvent or in the presence of an solvent, preferable a solvent that is inert under the respective reaction conditions. Suitable inert solvents for carrying out the reaction are known in the art.

Some of the starting materials of the formula XI and/or the formula XII are known and preferably commercially available. If they are not known, they can be prepared by methods known per se.

Independently of the chosen reaction route, it is in many cases possible or even feasible to introduce residues R⁸, R⁹ and/or R¹⁰ into one or more of the compounds described above, or, if the compound already comprises one or more residues R⁸, R⁹ and/or R¹⁰, to introduce additional residues R⁸, R⁹ and/or R¹⁰ into said compound. The introduction of additional residues can be readily performed by methods known in the art and especially by aromatic substitution, for example nucleophilic aromatic substitution or electrophilic aromatic substitution. For example, in compounds comprising Ar¹, wherein Ar¹ comprises one or more halogen and preferably fluorine substituents, one or more of the halogen/fluorine substituents can be easily substituted by hydroxy, thio and/or amino substituted hydrocarbons, preferably selected from the group consisting of HO(CH₂)_(n)NRR¹¹R¹², HO(CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², HO(CH₂)_(n)NR¹¹(CH₂)_(k)OR¹², HO(CH₂)_(n)NR¹¹(CH₂)_(k)NR¹¹R¹², HO(CG₂)_(n)COOR¹³, HO(CH₂)_(n)S(O)_(u)R¹³HNR¹¹(CH₂)_(n)NR¹¹R¹², HNR¹¹(CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², HNR¹¹(CH₂)_(n)NR¹¹(CH₂)_(k)OR¹², HNR¹¹(CH₂)_(n)NR¹¹(CH₂)_(k)NR¹¹R¹², HNR¹¹(CH₂)_(n)COOR¹² and HNR¹¹(CH₂)_(n)S(O)_(u)R¹³ wherein R¹¹, R¹² and R¹³ are defined as above and n is as defined above, preferably n is 0, 1 or 2 and especially is 0, k is 1 to 4 and preferably 1 or 2, and u is preferably 2. In this embodiment R¹¹, R¹² and R¹³ are more preferably selected independently from each other from the group consisting of H, methyl and ethyl. Even more preferred, the hydroxy, thio and/or amino substituted hydrocarbons are selected from the group consisting of NH₃, HN(CH₃)₂, NH₂CH₃, HN(C₂H₅)₂, H₂NCH₂CH₂NH₂, HOCH₂CH₂NH₂, HOCH₂CH₂NHCH₃, HN(CH₃)CH₂CH₂NH₂, HN(CH₃)CH₂CH₂N(CH₃)₂, HN(CH₃)CH₂CH₂N(CH₃)₂, HN(CH₃)CH₂CH₂OCH₃, HOCH₂CH₂N(CH₃)₂, HOCH₂CH₂N(CH₂CH₃)₂, HSCH₃, HSC₂H₅, and compounds of the formulae

or salts and especially metal salts thereof.

On the other hand, it is in many cases possible or even feasible to modify or derivatize one or more of the residue is R⁸, R⁹ and R¹⁰ into residues R⁸, R⁹ and/or R¹⁰ other than the ones originally present. For example, CH₃— groups can be oxidized into aldehyde groups or carbonic acid groups, thio atom containing groups, for example S-alkyl or S-aryl groups, can be oxidized into SO₂-alkyl or SO₂-aryl-groups, respectively, carboxylic acid groups can be derivatized to carboxylic acid ester groups or carboxylic acid amide groups and carboxylic acid ester groups or carboxylic acid amide groups can be hydrolysed into the corresponding carboxylic acid groups. Methods for performing such modifications or derivatizations are known in the art, for example from Houben-Weyl, Methods of Organic Chemistry.

Every reaction step described herein can optionally be followed by one or more working up procedures and/or isolating procedures. Suitable such procedures are known in the art, for example from standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart) Examples for such procedures include, but are not limited to evaporating a solvent, distilling, crystallization, fractionised crystallization, extraction procedures, washing procedures, digesting, filtration procedures chromatography and chromatography by HPLC.

A base of the formula I or the formula II can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in a preferably inert solvent, such as ethanol, followed by evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as, for example, orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylic acid, p-toluene-sulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid, cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalenemono- and -disulfonic acids or laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the formula I. On the other hand, compounds of the formula I can be converted into the corresponding metal salts, in particular alkali metal salts or alkaline earth metal salts, or into the corresponding ammonium salts, using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate). Suitable salts are furthermore substituted ammonium salts, for example the dimethyl-, diethyl- and diisopropyl-ammonium salts, monoethanol-, diethanol- and diisopropanolammonium salts, cyclohexyl- and dicyclohexylammonium salts, dibenzylethylenediammonium salts, furthermore, for example, salts with arginine or lysine.

On the other hand, if desired, the free bases of the formula I or the formula II can be liberated from their salts using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate).

The invention relates to compounds of the formula I and of the formula II and physiologically acceptable salts and solvates thereof as medicaments.

The invention also relates to the compounds for the formula I and of the formula II and physiologically acceptable salts and solvates thereof as kinase inhibitors.

The invention furthermore relates to the use of the compounds of the formula I and/or physiologically acceptable salts and/or solvates thereof for the preparation of pharmaceutical compositions and/or pharmaceutical preparations, in particular by non-chemical methods. The invention furthermore relates to the use of the compounds of the formula II and/or physiologically acceptable salts and/or solvates thereof for the preparation of pharmaceutical compositions and/or pharmaceutical preparations, in particular by non-chemical methods. In this cases, one or more compounds according to the invention can be converted into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or adjuvant and, if desired, in combination with one or more further active ingredients.

The invention further relates to the use of one or more of the compounds according to the invention, selected from the group consisting of compounds of the formula I as free bases, solvates of compounds of the formula I, salts of compounds of formula I, of compounds of the formula II as free bases, solvates of compounds of the formula II and salts of compounds of formula II, for the production of pharmaceutical compositions and/or pharmaceutical preparations, in particular by a non-chemical route. In general, non-chemical routes for the production of pharmaceutical compositions and/or pharmaceutical preparations comprise processing steps on suitable mechanical means known in the art that transfer one or more compounds according to the invention into a dosage form suitable for administration to a patient in need of such a treatment. Usually, the transfer of one or more compounds according to the invention into such a dosage form comprises the addition of one or more compounds, selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients other than the compounds according to the invention. Suitable processing steps include, but are not limited to combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, casting and/or compressing the respective active and non-active ingredients. In this respect, active ingredients are preferably at least one compound according to this invention and one or more additional compounds other than the compounds according to the invention, which show valuable pharmaceutical properties, preferably those pharmaceutical active agents other than the compounds according to invention which are disclosed herein.

The process for preparing pharmaceutical compositions and/or pharmaceutical preparations preferably comprises one or more processing steps, selected from the group consisting of combining, milling, mixing, granulating, dissolving, dispersing, homogenizing and compressing. The one or more processing steps are preferably performed on one or more of the ingredients which are to form the pharmaceutical composition and/or pharmaceutical preparation preferably according to invention. Even more preferred, said processing steps are performed on two or more of the ingredients which are to form the pharmaceutical composition and/or pharmaceutical preparation, said ingredients comprising one or more compounds according to the invention and, additionally, one or more compounds, preferably selected from the group consisting of active ingredients other than the compounds according to the invention, excipients, auxiliaries, adjuvants and carriers. Mechanical means for performing said processing steps are known in the art, for example from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition.

Preferably, one or more compounds according to the invention are converted into a suitable dosage form together with at least one compound selected from the group consisting of excipients, auxiliaries, adjuvants and carriers, especially solid, liquid and/or semi-liquid excipients, auxiliaries, adjuvants and carriers, and, if desired, in combination with one or more further active ingredients.

Suitable dosage forms include, but are not limited to tablets, capsules, semi-solids, suppositories, aerosols, which can be produced according to methods known in the art, for example as described below:

-   tablets mixing of active ingredient/s and auxiliaries, compression     of said mixture into tablets (direct compression), optionally     granulation of part of mixture before compression -   capsules mixing of active ingredient/s and auxiliaries to obtain a     flowable powder, optionally granulating powder, filling     powders/granulate into opened capsules, capping of capsules -   semi-solids (ointments, gels, creams) dissolving/dispersing active     ingredient/s in an aqueous or fatty carrier; subsequent mixing of     aqueous/fatty phase with complementary fatty resp. aqueous phase,     homogenisation (creams only) -   suppositories (rectal and vaginal) dissolving/dispersing active     ingredient/s in carrier material liquified by heat (rectal: carrier     material normally a wax; vaginal: carrier normally a heated solution     of a gelling agent), casting said mixture into suppository forms,     annealing and withdrawal suppositories from the forms -   aerosols: dispersing/dissolving active agent/s in a propellant,     bottling said mixture into an atomizer

The invention thus relates to pharmaceutical compositions and/or pharmaceutical preparations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts and/or solvates and especially to pharmaceutical compositions and/or pharmaceutical preparations comprising at least one compound of the formula II and/or one of its physiologically acceptable salts and/or solvates.

Preferably, the pharmaceutical compositions and/or pharmaceutical preparations according to the invention contain a therapeutic effective amount of one or more compounds according to the invention. Said therapeutic effective amount of one or more of the compounds according to the invention is known to the skilled artisan or can be easily determined by standard methods known in the art. For example, the compounds according to the invention can be administered to a patient in an analogous manner to other compounds that are effective as raf-kinase inhibitors. Usually, suitable doses that are therapeutically effective lie in the range between 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500 mg and especially between 0.5 and 100 mg per dose unit. The daily dose comprises preferably more than 0.001 mg, more preferred more than 0.01 milligram, even more preferred more than 0.1 mg and especially more than 1.0 mg, for example more than 2.0 mg, more than 5 mg, more than 10 mg, more than 20 mg, more than 50 mg or more than 100 mg, and preferably less than 1500 mg, more preferred less than 750 my, even more preferred less than 500 my, for example less than 400 mg, less than 250 mg, less than 150 mg, less than 100 mg, less than 50 mg or less than 10 mg.

The specific dose for the individual patient depends, however, on the multitude of factors, for example on the efficacy of the specific compounds employed, on the age, body weight, general state of health, the sex, the kind of diet, on the time and route of administration, on the excretion rate, the kind of administration and the dosage form to be administered, the pharmaceutical combination and severity of the particular disorder to which the therapy relates. The specific therapeutic effective dose for the individual patient can readily be determined by routine experimentation, for example by the doctor or physician which advises or attends the therapeutic treatment.

However, the specific dose for each patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and method of administration, on the rate of excretion, medicament combination and severity of the particular illness to which the therapy applies. Parenteral administration is preferred. Oral administration is especially preferred.

These compositions and/or preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc or vaseline. Examples for suitable dosage forms, which are especially suitable for oral administration are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops. Further examples for suitable dosage forms, which are especially suitable for rectal administration are suppositories, further examples for suitable dosage forms, which are especially suitable for parenteral administration are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical application are ointments, creams or powders. The novel compounds may also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations. The compositions and/or preparations indicated may be sterilized and/or comprise assistants, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes and flavors and/or one or more further active ingredients, for example one or more vitamins.

For administration as an inhalation spray, it is possible to use sprays in which the active ingredient is either dissolved or suspended in a propellant gas or propellant gas mixture (for example CO₂ or chlorofluorocarbons), The active ingredient is advantageously used here in micronized form, in which case one or more additional physiologically acceptable solvents may be present, for example ethanol. Inhalation solutions can be administered with the aid of conventional inhalers.

The compounds of the formula I and their physiologically acceptable salts and solvates and especially the compounds of formula II and their physiologically acceptable salts and solvates can be employed for combating one or more diseases, for example allergic diseases, psoriasis and other skin diseases, especially melanoma, autoimmune diseases, such as, for example, rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis.

In general, the substances according to the invention are preferably administered in doses corresponding to the compound rolipram of between 1 and 500 mg, in particular between 5 and 100 mg per dosage unit. The daily dose is preferably between about 0.02 and 10 mg/kg of body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and method of administration, on the excretion rate, medicament combination and severity of the particular illness to which the therapy applies.

The compounds of the formula I according to claim 1 and/or their physiologically acceptable salts are also used in pathological processes which are maintained or propagated by angiogenesis, in particular in tumours, restenoses, diabetic retinopathy, macular degenerative disease or rheumatoid arthritis.

Those of skill will readily appreciate that dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Some of the specific compounds are more potent than others. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

For use in the subject methods, the subject compounds may be formulated with pharmaceutically active agents other than the compounds according to the invention, particularly other anti-metastatic, antitumor or anti-angiogenic agents. Angiostatic compounds of interest include angiostatin, enclostatin, carboxy terminal peptides of collagen alpha (XV), etc. Cytotoxic and cytostatic agents of interest include adriamycin, aleran, Ara-C, BICNU, busulfan, CNNU, cisplatinum, cytoxan, daunorubicin, DTIC, 5-FU, hydrea, ifosfamicle, methotrexate, mithramycin, mitomycin, mitoxantrone, nitrogen mustard, velban, vincristine, vinblastine, VP-16, carboplatinum, fludarabine, gemcitabine, idarubicin, irinotecan, leustatin, navelbine, taxol, taxotere, topotecan, etc.

The compounds of the invention preferably show antiproliferative effects, for example in an in vivo xenograft tumor model. The subject compounds can be administered to a subject having a hyperproliferative disorders, e.g., to inhibit tumor growth, to decrease inflammation associated with a lymphoproliferative disorder, to inhibit graft rejection, or neurological damage due to tissue repair, etc. The present compounds can be useful for prophylactic or therapeutic purposes. As used herein, the term “treating” is used to refer to both prevention of disease, and treatment of pre-existing conditions. The prevention of proliferation is accomplished by administration of the subject compounds prior to development of overt disease, e.g., to prevent the regrowth of tumors, prevent metastatic growth, diminish restenosis associated with cardiovascular surgery, etc. Alternatively the compounds are used to treat ongoing disease, by stabilizing or improving the clinical symptoms of the patient.

Furthermore, the compounds according the invention preferably can be utilized in the treatment of infectious diseases of diverse genesis.

Infections according the invention include, but are not limited to infections caused by pathogenic microorganisms, such as bacteria, fungi, viruses and protozoans, for example influenza (Pleschka, S. et al. Nature, Cell Biol. 2001, 3, page 301-305), retroviruses, for example HIV infection (Yang, X. et al. J. Biol. Chem. 1999, 274, page 27981-27988; Popik, W et al Mol Cel Biol. 1996, 16, page 6532-6541), Hepatitis B (Benn, J et al., Proc. Natl. Acad. Sci. 1995, 92, page 11215-11219), Hepatitis C (Aoki et al. J. Virol. 2000, 74, page 1736-1741), papillomavirus, parainfluenza, rhinoviruses, adenoviruses, Heliobacter pylori, and viral and bacterial infections of the skin (e.g. cold sores, warts, chickenpox, molluscum. contagiosum, herpes zoster, boils, cellulitis, erysipelas, impetigo, tinea, Athlete's foot and ringworm).

Furthermore, the compounds according the invention preferably show anti-angiogenic properties.

Thus, compounds of the present invention can be advantageously employed in the treatment of one or more diseases afflicting mammals which are characterized by cellular proliferation in the area of disorders associated with neo-vascularization and/or vascular permeability including blood vessel proliferative disorders including arthritis and restenosis; fibrotic disorders including hepatic cirrhosis and atherosclerosis; mesangial cell proliferative disorders include glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection and glomerulopathies; and metabolic disorders include psoriasis, diabetes mellitus, chronic wound healing, inflammation and neurodegenerative diseases.

The host, or patient may be from any mammalian species, e.g., primate sp., particularly human; rodents, including mice, rats and hamsters; rabbits; equines, bovines, canines, felines; etc. Animal models are of interest for experimental investigations, providing a model for treatment of human disease.

The susceptibility of a particular cell to treatment with the subject compounds may be determined by in vitro testing. Such in vitro testing methods are known in the art. For example, they can be performed as described herein or in the literature cited herein, or in an analogous manner thereof. Typically a culture of the cell is combined with a subject compound at varying concentrations for a period of time sufficient to allow the active agents to induce cell death or inhibit migration, usually between about one hour and one week. For in vitro testing, cultured cells from a biopsy sample may be used. The viable cells left after treatment are then counted.

The dose will vary depending on the specific compound utilized, specific disorder, patient status, etc. Typically a therapeutic dose will be sufficient to substantially decrease the undesirable cell population in the targeted tissue, while maintaining patient viability, Treatment will generally be continued until there is a substantial reduction, e.g., at least about 50% decrease in the cell burden, and may be continued until there are essentially none of the undesirable cells detected in the body.

The compounds according to the invention are preferably administered to human or nonhuman animals, more preferred to mammalian animals and especially to humans.

The compounds also find use in the specific inhibition of a signaling pathway mediated by protein kinases. Protein kinases are involved in signaling pathways for such important cellular activities as responses to extracellular signals and cell cycle checkpoints. Inhibition of specific protein kinases provided a means of intervening in these signaling pathways, for example to block the effect of an extracellular signal, to release a cell from cell cycle checkpoint, etc. Defects in the activity of protein kinases are associated with a variety of pathological or clinical conditions, where there is a defect in the signaling mediated by protein kinases. Such conditions include those associated with defects in cell cycle regulation or in response to extracellular signals, e.g., immunological disorders, autoimmune and immunodeficiency diseases; hyperproliferative disorders, which may include infection, psoriasis, arthritis, inflammation, endometriosis, scarring, cancer, etc. The compounds of the present invention are active in inhibiting purified kinase proteins preferably raf kinases, e.g., there is a decrease in the phosphorylation of a specific substrate in the presence of the compound. The compounds of the invention may also be useful as reagents for studying signal transduction or any of the clinical disorders listed throughout this application.

There are many disorders associated with a dysregulation of cellular proliferation. The conditions of interest include, but are not limited to, the following conditions. The subject compounds are useful in the treatment of a variety of conditions where there is proliferation and/or migration of smooth muscle cells, and/or inflammatory cells into the intimal layer of a vessel, resulting in restricted blood flow through that vessel, e.g., neointimal occlusive lesions. Occlusive vascular conditions of interest include atherosclerosis, graft coronary vascular disease after transplantation, vein graft stenosis, peri-anastomatic prothetic graft stenosis, restenosis after angioplasty or stent placement, and the like.

Diseases where there is hyperproliferation and tissue remodelling or repair or reproductive tissue, e.g., uterine, testicular and ovarian carcinomas, endometriosis, squamous and glandular epithelial carcinomas of the cervix, etc. are reduced in cell number by administration of the subject compounds. The growth and proliferation of neural cells is also of interest.

Tumor cells are characterized by uncontrolled growth, invasion to surrounding tissues, and metastatic spread to distant sites. Growth and expansion requires an ability not only to proliferate, but also to down-modulate cell death (apoptosis) and activate angiogenesis to produce a tumor neovasculature.

Tumors of interest for treatment include carcinomas, e.g., colon, duodenal, prostate, breast, melanoma, ductal, hepatic, pancreatic, renal, endometrial, stomach, dysplastic oral mucosa, polyposis, invasive oral cancer, non-small cell lung carcinoma, transitional and squamous cell urinary carcinoma etc.; neurological malignancies; e.g. neuroplastoma, gliomas, etc.; hematological malignancies, e.g., childhood acute leukaemia, non-Hodgkin's lymphomas, chronic lymphocytic leukaemia, malignant cutaneous T-cells, mycosis fungoides, non-MF cutaneous T-cell-lymphoma, lymphomatoid papulosis, T-cell rich cutaneous lymphoid hyperplasia, bullous pemphigoid, discoid lupus erythematosus, lichen planus, etc.; and the like.

Tumors of neural tissue are of particular interest, e.g., gliomas, neuromas, etc. Some cancers of particular interest include breast cancers, which are primarily adenocarcinoma subtypes. Ductal carcinoma in situ is the most common type of noninvasive breast cancer. In DCIS, the malignant cells have not metastasized through the walls of the ducts into the fatty tissue of the breast. Infiltration (or invasive) ductal carcinoma (IDC) has metastasized through the wall of the duct and invaded the fatty tissue of the breast. Infiltrating (or invasive) lobular carcinoma (ILC) is similar to IDC, in that it has the potential to metastasize elsewhere in the body. About 10% to 15% of invasive breast cancers are invasive lobular carcinomas.

Also of interest is non-small cell lung carcinoma. Non-small cell lung cancer (NSCLC) is made up of three general subtypes of lung cancer. Epidermoid carcinoma (also called squamos cell carcinoma) usually starts in one of the larger bronchial tubes and grows relatively slowly. The size of these tumors can range from very small to quite large. Adenocarcinoma starts growing near the outside surface of the lung and may vary in both size and growth rate. Some slowly growing adenocarcinomas are described as alveolar cell cancer. Large cell carcinoma starts near the surface of the lung, grows rapidly, and the growth is usually fairly large when diagnosed. Other less common forms of lung cancer are carcinoid, cylindroma, mucoepidermoid, and malignant mesothelioma.

Melanoma is a malignant tumor of melanocytes. Although most melanomas arise in the skin, they also may arise from mucosal surfaces or at other sites to which neural crest cells migrate. Melanoma occurs predominantly in adults, and more than half of the cases arise in apparently normal areas of the skin. Prognosis is affected by clinical and histological factors and by anatomic location of the lesion. Thickness and/or level of invasion of the melanoma, mitotic index, tumor infiltrating lymphocytes, and ulceration or bleeding at the primary site affect the prognosis. Clinical staging is based on whether the tumor has spread to regional lymph nodes or distant sites. For disease clinically confined to the primary site, the greater the thickness and depth of local invasion of the melanoma, the higher the chance of lymph node metastases and the worse the prognosis. Melanoma can spread by local extension (through lymphatics) and/or by hematogenous routes to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites.

Other hyperproliferative diseases of interest relate to epidermal hyperproliferation, tissue, remodeling and repair. For example, the chronic skin inflammation of psoriasis is associated with hyperplastic epidermal keratinocyctes as well as infiltrating mononuclear cells, including CD4+ memory T cells, neutrophils and macrophages.

The proliferation of immune cells is associated with a number of autoimmune and lymphoproliferative disorders. Diseases of interest include multiple sclerosis, rheumatoid arthritis and insulin dependent diabetes mellitus. Evidence suggests that abnormalities in apoptosis play a pan in the pathogenesis of systemic lupus erythematosus (SLE). Other lymphoproliferative conditions the inherited disorder of lymphocyte apoptosis, which is an autoimmune lymphoproliferative syndrome, as well as a number of leukemia's and lymphomas. Symptoms of allergies to environmental and food agents, as well as inflammatory bowel disease, may also be alleviated by the compounds of the invention.

Surprisingly, it has been found that glycine amide derivatives according to invention are able to interact with signaling pathways, especially the signaling pathways described herein and preferably the raf-kinase signaling pathway. Glycine amide derivatives according to the invention preferably show advantageous biological activity which can easily be demonstrated according to methods known in the art, for example by enzyme based assays. Suitable assays are known in the art, for example from the literature cited herein and the references cited in the literature, or can be developed and/or performed in an analogous manner thereof. In such enzyme based assays, glycine amide derivatives according to invention show an effect, preferably a modulating and especially an inhibiting effect which is usually documented by IC₅₀ values in a suitable range, preferably in the micromolar range and more preferred in the nanomolar range.

In general, compounds according to the invention are to be regarded as suitable kinase-modulators and especially suitable kinase-inhibitors according to the invention if they show an effect or an activity to one or more kinases, preferably to one or more raf-kinases that preferably lies, determined as IC₅₀-value, in the range of 100 μmol or below, preferably 10 μmol or below, more preferably in the range of 3 μmol or below, even more preferably in the range of 1 μmol or below and most preferably in the nanomolar range. Especially preferred for use according to the invention are kinase-inhibitors as defined above/below, that show an activity, determined as IC₅₀-value; to one or more raf-kinases, preferably including A-raft, B-rat and c-raf1 or consisting of A-raf, B-raf and c-raf1 and more preferred including c-raft or consisting of c-raf1, in the range of 0.5 μmol or below and especially in the range of 0.1 μmol or below. In many cases an IC₅₀-value at the lower end of the given ranges is advantageous and in some cases it is highly desirable that the IC₅₀-value is as small as possible or the he IC₅₀-values are as small as possible, but in general IC₅₀-values that lie between the above given upper limits and a lower limit in the range of 0.0001 μmol, 0.001 μmol, 0.01 μmol or even above 0.1 μmol are sufficient to indicate the desired pharmaceutical activity. However, the activities measured can vary depending on the respective testing system or assay chosen.

As discussed herein, these signaling pathways are relevant for various disorders. Accordingly, by interacting with one or more of said signaling pathways, glycine amide derivatives are useful in the prevention and/or the treatment of disorders that are dependent from said signaling pathways.

Subject of the present invention are therefore glycine amide derivatives according to the invention as promoters or inhibitors, preferably as inhibitors, of the signaling pathways described herein. Preferred subject of the invention are therefore glycine amide derivatives according to the invention as promoters or inhibitors, preferably as inhibitors of the raf-kinase pathway. More preferred subject of the invention are therefore glycine amide derivatives according to the invention as promoters or inhibitors, preferably as inhibitors of the raf-kinase. Even more preferred subject of the invention are glycine amide derivatives according to invention as promoters or inhibitors, preferably as inhibitors, of one or more raf-kinases, selected from the group consisting of A-raft, B-raf and c-raf1. Especially preferred subject of the invention are glycine amide derivatives according to the invention as promoters or inhibitors, preferably as inhibitors of c-raf1.

Thus, subject of the present invention are glycine amide derivatives according to the invention as medicaments. Subject of the present invention are glycine amide derivatives according to the invention as medicament active ingredients. Further subject of the present invention is the use of one or more glycine amide derivatives according to the invention as a pharmaceutical. Further subject of the present invention is the use of one or more glycine amide derivatives according to the invention in the treatment and/or the prophylaxis of disorders, preferably the disorders described herein, more preferred disorders that are caused, mediated and/or propagated by signalling pathways discussed herein, even more preferred disorders that are caused, mediated and/or propagated by raf-kinases and especially disorders that are caused, mediated and/or propagated by raf-kinases, selected from the group consisting of A-raf, B-raf and c-raf1. Usually, the disorders discussed herein are divided into two groups, hyperproliferative and non hyperproliferative disorders. In this context, infection, psoriasis, arthritis, inflammation, endometriosis, scarring, begnin prostatic hyperplasia, immunological diseases, autoimmune diseases and immunodeficiency diseases are to be regarded as noncancerous disorders, of which infections, arthritis, inflammation, immunological diseases, autoimmune diseases and immunodeficiency diseases are usually regarded as non hyperproliferative disorders. In this context, brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer, renal cancer, colorectal cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynaecological cancer, thyroid cancer, lymphoma, chronic leukaemia and acute leukaemia are to be regarded as cancerous disorders, all of which are usually regarded as hyperproliferative disorders. Especially cancerous cell growth and especially cancerous cell growth mediated by raf-kinase is a disorder which is a target of the present invention. Subject of the present invention therefore are glycine amide derivatives according to the invention as medicaments and/or medicament active ingredients in the treatment and/or the prophylaxis of said disorders and the use of glycine amide derivatives according to the invention for the manufacture of a pharmaceutical for the treatment and/or the prophylaxis of said disorders as well as a method of treatment of said disorders, comprising administering one or more glycine amide derivatives according to the invention to a patient in need of such an administration.

Accordingly, subject of the present invention are pharmaceutical compositions that contain one or more glycine amide derivatives according to the invention. Subject of the present invention are especially pharmaceutical compositions that contain one or more glycine amide derivatives according to the invention and one or more additional compounds (other than the compounds of the instant invention), preferably selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants, carriers and pharmaceutically active ingredients other than the compounds according to the invention.

Accordingly, subject of the present invention is a process for the manufacture of a pharmaceutical composition, wherein one or more glycine amide derivatives according to the invention and one or more compounds (other than the compounds of the instant invention), preferably selected from the group consisting of carriers, excipients, auxiliaries, adjuvants and pharmaceutically active ingredients other than the compounds according to the invention.

Accordingly, the use of the compounds according to the invention in the treatment of hyperproliferative disorders is a subject of the instant invention.

Accordingly, the use of the compounds according to the invention for producing a medicament for the treatment of hyperproliferative disorders is a subject of the instant invention.

Above and below, all temperatures are given in ° C. In the examples below, “conventional workup” means that the organic phase is washed with saturated NaHCO₃ solution, if desired with water and saturated NaCl solution, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel, by preparative HPLC and/or by crystallization.

The present invention relates to glycinamide derivatives of formula I, the use of the compounds of formula I as inhibitors of raf-kinase, the use of the compounds of formula I for the manufacture of a pharmaceutical composition and a method of treatment, comprising administering said pharmaceutical composition to a patient.

EXAMPLES 4-(4-Pyridinyloxy)-phenylamine (2)

-   a) In a reaction apparatus equipped with a stirring means and a     cooler, 195 g (1.4 mol) 4-nitrophenol and 445.2 g (1.4 mol)     bipyridin are slowly heated up to a temperature of 150° C. under     agitation. After three hours of stirring at 150° C., the hot     reaction mixture is poured into ice-cool water, acidified with     hydrochloric acid and washed with methyl tert.-butyl ether (2×3 l).     The organic phase is turned basic (pH about 12) by addition of     concentrated caustic soda solution and extracted with methyl     tert.-butyl ether (2×3 l). The combined, organic phases are washed     with water (4×1 l), dried over Na₂SO₄, filtered and evaporated. The     residue is dissolved in 100 ml ether, cooled in an ice bath and     caused to crystallize by addition of petroleum ether (200 ml). The     crystalline residue is collected by suction and dried in vacuum to     yield 75 g (25%) brownish crystals of 1. -   b) Compound 1 is hydrogenated with Pd/C in methanol. The reaction     mixture is filtered over kieselguhr, the residue washed with     methanol and the filtrate evaporated. The residue is digested with a     diethyl ether/petroleum ether-mixture (2:1), filtered by suction,     washed with petrol ether and dried in vaccuo at 40° C. overnight to     yield 50.94 g (76%) brownish crystals of 2.

3-(4-Pyridinyloxy)-phenylamine (4)

-   a) In a reaction apparatus equipped with a stirring means and a     cooler, 200 g (1.44 mol/l) 3-nitrophenol and 457.93 g (1.44 mol)     bipyridin are slowly heated up to a temperature of 150° C. under     agitation. After three hours of stirring at 150° C., the hot     reaction mixture is poured into ice-cool water, acidified with     hydrochloric acid and washed with methyl tert.-butyl ether (2×3 l).     The organic phase is turned basic (pH about 12) by addition of     concentrated caustic soda solution and extracted with methyl     tert.-butyl ether (2×3 l). The combined organic phases are washed     with water (4×1 l), dried over Na₂SO₄, filtered and evaporated. The     residue is dissolved in 200 ml diethyl ether, treated with charcoal     (20 g) for 1 h under stirring and filtered. The filtrate is     evaporated to about 200 ml, cooled in a ice bath and caused to     crystallize by addition of petroleum ether (500 ml). The crystalline     residue is collected by suction and dried in vacuum to yield 131 g     (42%) light brownish crystals of 3. -   b) Compound 3 is hydrogenated with Pd/C in methanol. The reaction     mixture is filtered over kieselguhr, the residue washed with     methanol and the filtrate evaporated. The residue is digested with     diethyl ether, filtered by suction, washed with diethyl ether and     dried in vacuum at 40° C. overnight to yield 98.08 g (87%) light     brownish crystals of 4.

4-(3-Pyridinyloxy)-phenylamine

-   a) In a reaction apparatus equipped with a stirring means and a     cooler, 125 g (0.94 mol) 3-hydroxypyridine, potassium salt, 300 g     1-chloronitrobenzene and 15 g copper are heated up to a temperature     of 180° C. under agitation for homogenization. After three hours of     stirring at 180° C., the reaction mixture is cooled to 90° C. and     methyl-tert.-butyl ether is added quickly. The resulting suspension     is further stirred for 1 h, filtered by suction and the filtrate is     extracted with 10% aqueous hydrochloric acid (3×1 l). The resulting     aqueous phase is made alkaline with ammonium hydroxide solution and     extracted with ethyl acetate. The obtained organic phase is dried     over Na₂SO₄, filtered and evaporated in vacuum. The residue is     purified by column chromatography on silica gel (1 kg) with     dichloromethan as eluent, dissolved in 10% aqueous hydrochloric acid     and extracted with ethyl acetate. The aqueous phase is made alkaline     with ammonium hydroxide solution and the resulting crystalline     precipitate is collected by suction, washed with little cold water     and dried on air for 4 days to yield 44.7 g (22%) brownish crystals     of 5. -   b) Compound 5 is hydrogenated with Pd/C in methanol/tetrahydrofurane     at room temperature. The reaction mixture is filtered over     kieselguhr, the residue washed with methanol and the filtrate     evaporated. The residue is digested with diethyl ether, filtered by     suction, washed with diethyl ether and dried in vacuum at 40° C.     overnight to yield 37.14 g (95%) light brownish crystals of 6.

3-(Pyridinyloxy)-phenylamine (8)

-   a) In a reaction apparatus equipped with a stirring means and a     cooler, 50 g (0.53 mol) 3-hydroxypyridine, 178.8 g (1.05 mol)     1,3-dinitrobenzene and 159.9 g (1.16 mol) K₂CO₃ are suspended in 1.4     l dimethyl formamide (DMF) and heated to 150° C., After 16 hours     stirring at 150° C., the reaction mixture is cooled to room     temperature and evaporated. The residue is treated with ethyl     acetate (1.5 l) under stirring for 30 minutes, filtered and the     filtrate is extracted with 10% aqueous hydrochloric acid. The     aqueous phase is made alkaline with ammonium hydroxide solution and     extracted with ethyl acetate. The combined organic phases our dried     over Na₂SO₄, filtered and evaporated. The residue is purified by     column chromatography on silica gel (1 kg) with dichloromethane as     eluent, dissolved in 10% aqueous hydrochloric acid and extracted     with ethyl acetate. The aqueous phase is made alkaline with ammonium     hydroxide solution and extracted with ethyl acetate. The combined     organic phases are dried over Na₂SO₄, filtered and evaporated to     yield 98 g (86%) brownish oil of 7. -   b) Compound 7 is hydrogenated with Pd/C in methanol/tetrahydrofurane     at room temperature. The reaction mixture is filtered over     kieselguhr, the residue washed with methanol and the filtrate     evaporated. The residue is digested with a diethyl ether/petroleum     ether-mixture (2:1), filtered by suction, washed with petrol ether     and the resulting crystals are collected. The mother liquor is     evaporated to dryness and allowed to stand in the refrigerator     overnight. The resulting crystals where digested with a petroleum     ether/diethyl ether-mixture (9:1) and filtered by suction. The     combined crystalline residues are dried in vacuum at 40° C.     overnight to yield 77.7 g (91%) light brownish crystals of 8.

2-Chloro-N-(4-chloro-3-trifluoro methyl phenyl)-acetamide (9)

Chloroacetic acid chloride (0:69 ml; 8.44 mmol) is dropped slowly into a stirred solution of 4-chloro-3-trifluoro methyl aniline (1.5 g; 7.67 mmol) in pyridine (0.81 ml; 9.97 mmol) and dichloromethane (15 ml), cooled to 0° C. Stirring is continued for 2 h at room temperature. The reaction mixture is diluted with dichloromethane, washed twice with 1N aqueous hydrochloric acid and with water. The reaction mixture is then dried over Na₂SO₄, filtered and evaporated to yield 2.05 g (98%) brownish solid of 9.

N-(4-Chloro-3-trifluoro methyl phenyl)-2-[4-(4-pyridinyloxy)phenyl amino]-acetamide

A solution of 146.1 mg (0.54 mmol) of compound 9 in dimethylformamide (DMF) is given to a solution of 100 mg (0.54 mmol) of compound 2 and 0.1 ml (0.59 mmol) N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100° C. for 6 h, then evaporated and the residue is purified by preparative HPLC to yield 10.7 mg (5%) colourless solid.

N-(4-Chloro-3-trifluoro methyl phenyl)-2[3-(4-pyridinyloxy)phenyl amino]-acetamide

A solution of 146.1 mg (0.54 mmol) of compound 9 in dimethylformamide (DMF) is given to a solution of 100 mg (0.54 mmol) of compound 4 and 0.1 ml (0.59 mmol) N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100° C. for 6 h, then evaporated and the residue is purified by preparative HPLC to yield 110 mg (48%) colourless solid.

N-(4-Chloro-3-trifluoro methyl phenyl)-2-[4-(3-pyridinyloxy)phenyl amino]-acetamide

A solution of 146.1 mg (0.54 mmol) of compound 9 in dimethylformamide (DMF) is given to a solution of 100 mg (0.54 mmol) of compound 6 and 0.1 ml (0.59 mmol) N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100° C. for 4 h, then evaporated and the residue is purified by preparative HPLC to yield 20 mg (9%) colourless solid.

N-(4-Chloro-3-trifluoro methyl phenyl)-2-[3-(3-pyridinyloxy)phenylamine]-acetamide

A solution of 146.1 mg (0.54 mmol) of compound 9 in dimethylformamide (DMF) is given to a solution of 100 mg (0.54 mmol) of compound 8 and 0.1 ml (0.59 mmol) N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100° C. for 4 h, then evaporated and the residue is purified by preparative HPLC to yield 24 mg (11%) colourless solid.

N-(5-t-Butyl-3-isoxazolyl)-2-chloro-acetamide

Chloroacetic acid chloride (0.93 ml; 11.42 mmol) is dropped slowly into a stirred solution of 5-t-Butyl-3-amino isoxazole (1.5 g; 7.67 mmol) in pyridine (1.09 ml; 13.49 mmol) and dichloromethane (20 ml), cooled to 0° C. Stirring is continued for 2 h at room temperature. The reaction mixture is diluted with dichloromethane, washed twice with 1N aqueous hydrochloric acid, twice with an aqueous solution of NaHCO₃ and with water. The reaction mixture is then dried over Na₂SO₄, filtered and evaporated to yield 2.2 g (98%) brownish solid of 10.

N-(5-t-Butyl-3-isoxazolyl)-2-[4-(4-pyridinyloxy)phenyl amino]-acetamide

A solution of 58.2 mg (0.27 mmol) of compound 10 in dimethylformamide (DMF) is given to a solution of 50 mg (0.27 mmol) of compound 2 and 0.05 ml (0.3 mmol) N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100° C. for 4 h, then evaporated and the residue is purified by preparative HPLC to yield 28 mg (29%) colourless solid.

N-(5-t-Butyl-3-isoxazolyl)-2-[3-(4-pyridinyloxy)phenyl amino]-acetamide

A solution of 58.2 mg (0.27 mmol) of compound 10 in dimethylformamide (DMF) is given to a solution of 50 mg (0.27 mmol) of compound 4 and 0.05 ml (0.3 mmol) N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100° C. for 4 h, then evaporated and the residue is purified by preparative HPLC to yield 47 mg (48%) colourless solid.

N-(3-t-Butyl-5-isoxazolyl)-2-chloro-acetamide

Chloroacetic acid chloride (0.25 ml; 3.14 mmol) is dropped slowly into a stirred solution of 3-t-Butyl-5-amino isoxazole (400 my; 2.85 mmol) in pyridine (0.3 ml; 3.71 mmol) and dichloromethane (2 ml) cooled to 0° C. Stirring is continued for 2 h at room temperature. The reaction mixture is diluted with dichloromethane, washed twice with 1N aqueous hydrochloric acid, twice with an aqueous solution of NaHCO₃ and with water. The reaction mixture is then dried over Na₂SO₄, filtered and evaporated to yield 600 mg (97%) brownish solid of 11.

N-(3-t-Butyl-5-isoxazolyl)-2-[4-(4-pyridinyloxy)phenyl amino]-acetamide

A solution of 58.2 mg (0.27 mmol) of compound 11 in dimethylformamide (DMF) is given to a solution of so mg (0.27 mmol) of compound 2 and 0.05 ml (0.3 mmol)N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100° C. for 2 h, then evaporated and the residue is purified by preparative HPLC to yield 5.5 my (6%) colourless solid.

N-(3-t-Butyl-5-isoxazolyl)-2-[3-(4-pyridinyloxy)phenyl amino]-acetamide

A solution of 58.2 mg (0.27 mmol) of compound 11 in dimethylformamide (DMF) is given to a solution of 50 mg (0.27 mmol) of compound 4 and 0.05 ml (0.3 mmol) N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100° C. for 2 h, then evaporated and the residue is purified by preparative HPLC to yield 20 mg (20%) colourless solid.

The compounds (1) to (235) as described above can preferably be produced according to the procedures described herein or in an analogous manner thereof.

Example A Injection Vials

A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water using 2N hydrochloric acid, sterile-filtered, dispensed into injection vials, lyophilized under sterile conditions and aseptically sealed. Each injection vial contains 5 mg of active compound.

Example B Suppositories

A mixture of 20 g of an active compound of the formula I is fused with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of active compound.

Example C Solution

A solution of 1 g of an active compound of the formula I, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D Ointment

500 mg of an active compound of the formula I is mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E Tablets

A mixture of 1 kg of active compound of the formula 1, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed to give tablets in a customary manner such that each tablet contains 10 mg of active compound.

Example F Coated Tablets

Analogously to Example E, tablets are pressed and are then coated in a customary manner using a coating of sucrose, potato starch, talc, tragacanth and colourant.

Example G Capsules

2 kg of active compound of the formula I are dispensed into hard gelatin capsules in a customary manner such that each capsule contains 20 mg of the active compound.

Example H Ampoules

A solution of 1 kg of active compound of the formula I in 60 l of double-distilled water is sterile-filtered, dispensed into ampoules, lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active compound. 

1. A method for the treatment and/or prophylaxis of disorders in a patient caused, mediated and/or propagated by kinases, said method comprising administering to said patient one or more compounds according to formula I A-D-B  (I) wherein D is a bivalent glycine amide moiety, or a derivative thereof, A is an unsubstituted or substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L′)_(α); L is a 5, 6 or 7 membered cyclic structure containing 0-4 members selected from nitrogen, oxygen and sulfur bound directly to D; L′ comprises an optionally substituted cyclic moiety having at least 5 members and containing 0-4 members selected from nitrogen, oxygen and sulfur, wherein L′ is optionally substituted by at least one substituent selected from —SO_(β)R_(x) and —C(NR_(y))R_(z); M is a bond or a bridging group having at least one atom; α is an integer of from 1-4; B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms, comprising at least one 5-, 6-, or 7-membered cyclic structure, bound directly to D and containing 0-4 members selected from nitrogen, oxygen and sulfur; where when B is substituted, L is substituted or L′ is additionally substituted, the substituents are selected from halogen, up to per-halo, and Wγ; R_(y) is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo; R_(z) is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; R_(x) is R_(z) or NR_(a)R_(b); R_(a) and R_(b) are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or  —OSi(R_(f))₃ where R_(f) is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or b) R_(a) and R_(b) together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or c) one of R_(a) or R_(b) is —C(O)—, a C₁-C₅ divalent alkylene group or a substituted C₁-C₅ divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C₁-C₅ divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; γ is 0-3; W is, in each case, independently selected from —CN, —CO₂R, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵, —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the groups consisting of —CN, —CO₂R, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵, —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵ and halogen up to per-halo; R⁵ is, in each case, independently H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen; Q is —O—, —S—, —N(R⁵)—, —(CH₂)_(β), —C(O)—, —CH(OH)—, —(CH₂)_(β)O—, —(CH₂)_(β)S—, —(CH₂)_(β)N(R⁵)—, —O(CH₂)_(β), —CHHal-, —CHal₂-, —S—(CH₂)— or —N(R⁵)(CH₂)_(β)—; β is 1-3; Hal is halogen; Ar is 5- or 6-member aromatic structure containing 0-2 members selected from nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z_(δ1); δ1 is 0 to 3; and Z is, in each case, independently selected from —CN, —CO₂R⁵, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵, —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from —CN, —CO₂R⁵, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵, —NR⁵C(O)OR⁵, and —NR⁵C(O)R⁵; or a physiologically acceptable derivative, salts or solvate thereof.
 2. A method according to claim 1, wherein each M, independently from one another, represents a bond or is a bridging group selected from (CR⁵R⁵)_(h), and (CHR⁵)_(h)-Q-(CHR⁵)_(i), Q is O, S, N—R⁵, (CHal₂)_(j), (O—CHR⁵)_(j), (CHR⁵—O)_(j), CR⁵═CR⁵, (O—CHR⁵CHR⁵)_(j), (CHR⁵CHR⁵—O)_(j), C═O, C═S, C═NR⁵, CH(OR⁵), C(OR⁵)(OR⁵), C(═O)O, OC(═O), OC(═O)O, (C═O)N(R⁵)C(═O), OC(═O)N(R⁵), N(R⁵)C(═O)O, CH═N—NR⁵, S═O, SO₂, SO₂NR⁵, or NR⁵SO₂, h, i are independently from each other 0, 1, 2, 3, 4, 5, or 6, and j is 1, 2, 3, 4, 5 or
 6. 3. A method according to claim 1, selected from the compounds of formula II,

wherein Ar¹, Ar² are each, independently from one another, selected from aromatic hydrocarbons containing 6 to 14 carbon atoms and ethylenical unsaturated or aromatic heterocyclic residues containing 3 to 10 carbon atoms and one or two hetero atoms, independently selected from N, O and S, R⁸, R⁹ and R¹⁰ are independently selected from H, A, cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)OR¹¹, (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COOR¹², (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)NR¹¹COR¹³, (CH₂)_(n)NR¹¹CONR¹¹R¹², (CH₂)_(n)NR¹¹SO₂A, (CH₂)_(n)SO₂NR¹¹R¹², (CH₂)_(n)S(O)_(u)R¹³, (CH₂)_(n)OC(O)R¹³, (CH₂)_(n)COR¹³, (CH₂)_(n)SR¹¹, CH═N—OA, CH₂CH═N—OA, (CH₂)_(n)NHOA, (CH₂)_(n)CH═N—R¹¹, (CH₂)_(n)OC(O)NR¹¹R¹², (CH₂)_(n)NR¹¹COOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂OR¹³, (CH₂)_(n)N(R¹¹)CH₂CH₂OCF₃, (CH₂)_(n)N(R¹¹)C(R¹³)HCOOR¹², C(R¹³)HCOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂N(R¹²)CH₂COOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂NR¹¹R¹², CH═CHCOOR¹¹, CH═CHCH₂NR¹¹R¹², CH═CHCH₂NR¹¹R¹², CH═CHCH₂OR¹³, (CH₂)_(n)N(COOR¹¹)COOR¹², (CH₂)_(n)N(CONH₂)COOR¹¹, (CH₂)_(n)N(CONH₂)CONH₂, (CH₂)_(n)N(CH₂COOR¹¹)COOR¹², (CH₂)_(n)N(CH₂CONH₂)COOR¹¹, (CH₂)_(n)N(CH₂CONH₂)CONH₂, (CH₂)_(n)CHR¹³COR¹¹, (CH₂)_(n)CHR¹³COOR¹¹, (CH₂)_(n)CHR¹³CH₂OR¹⁴, (CH₂)_(n)OCN and (CH₂)_(n)NCO, R¹¹, R¹² are independently selected from H, A, (CH₂)_(m)Ar³ and (CH₂)_(m)Het, or, in NR¹¹R¹², R¹¹ and R¹² form, together with the N-Atom they are bound to, a 5-, 6- or 7-membered heterocycle which optionally contains 1 or 2 additional hetero atoms, selected from N, O an S, R¹³, R¹⁴ are independently selected from H, Hal, A, (CH₂)_(m)Ar⁴ and (CH₂)_(m)Het, A is selected from alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, alkoxy and alkoxyalkyl, Ar³, Ar⁴ are independently from one another aromatic hydrocarbon residues comprising 5 to 12 which are optionally substituted by one or more substituents, selected from A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶, COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵, SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵, Het is a saturated, unsaturated or aromatic heterocyclic residue which is optionally substituted by one or more substituents, selected from A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶, COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵, SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵, R¹⁵, R¹⁶ are independently selected from H, A, and (CH₂)_(m)Ar⁵, Ar⁵ is a 5- or 6-membered aromatic hydrocarbon which is optionally substituted by one or more substituents selected from methyl, ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN, OH, NH₂ and CF₃, k, n, m are independently of one another 0, 1, 2, 3, 4, or 5; X represents a bond or is (CR¹¹R¹²)_(h), or (CHR¹¹)_(h)-Q-(CHR¹²)_(i), Q is selected from O, S, N—R¹⁵, (CHal₂)_(j), (O—CHR¹⁸)_(j), (CHR¹⁸—O)_(j), CR¹⁸═CR¹⁹, (O—CHR¹⁸CHR¹⁹)_(j), CHR¹⁸CHR¹⁹—O)_(j), C═O, C═S, C═NR¹⁵, CH(OR¹⁵), C(OR¹⁷)(OR²⁰), C(═O)O, OC(═O), OC(═O)O, C(═)N(R¹⁵), N(R¹⁵)C(═O), OC(═O)N(R¹⁵), N(R¹⁵)C(═O)O, CH═N—O, CH═N—NR¹⁵, OC(O)NR¹⁵, NR¹⁵C(O)O, S═O, SO₂, SO₂NR¹⁵ and NR¹⁵SO₂, h, i are independently from each other 0, 1, 2, 3, 4, 5 or 6, j is 1, 2, 3, 4, 5 or 6, Y is selected from O, S, NR²¹, C(R²²)—NO₂, C(R²²)—CN and C(CN)₂, R²¹ is H, Hal, A, (CH₂)_(m)Ar⁴ and (CH₂)_(m)Het, R²² is H, A, (CH₂)_(m)Ar³ and (CH₂)_(m)Het, p, r are independently from one another 0, 1, 2, 3, 4 or 5, q is 0, 1, 2, 3 or 4, u is 0, 1, 2 or 3, and Hal is independently selected from F, Cl, Br and I; and the salts and solvates thereof.
 4. A method according to claim 1, wherein said compound is selected from the compounds of formulas IIa, IIb, IIc, IId, IIe, IIf, IIg and IIh,

wherein R⁸, R⁹ and R¹⁰ are independently selected from H, A, cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)OR¹¹, (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COOR¹², (CH₂)_(n)CONR¹¹R¹², (CH₂)₂NR¹¹COR¹³, (CH₂)_(n)NR¹¹CONR¹¹R¹², (CH₂)_(n)NR¹¹SO₂A, (CH₂)_(n)SO₂NR¹¹R¹², (CH₂)_(n)S(O)_(u)R¹³, (CH₂)_(n)OC(O)R¹³, (CH₂)_(n)COR¹³, (CH₂)_(n)SR¹¹, CH═N—OA, CH₂CH═N—OA, (CH₂)_(n)NHOA, (CH₂)_(n)CH═N—R¹¹, (CH₂)_(n)OC(O)NR¹¹R¹², (CH₂)_(n)NR¹¹COOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂OR¹³, (CH₂)_(n)N(R¹¹)CH₂CH₂OCF₃, (CH₂)_(n)N(R¹¹)C(R¹³)HCOOR¹², C(R¹³)HCOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂N(R¹²)CH₂COOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂NR¹¹R¹², CH═CHCOOR¹¹, CH═CHCH₂NR¹¹R¹², CH═CHCH₂NR¹¹R¹², CH═CHCH₂OR¹³, (CH₂)_(n)N(COOR¹¹)COOR¹², (CH₂)_(n)N(CONH₂)COOR¹¹, (CH₂)_(n)N(CONH₂)CONH₂, (CH₂)_(n)N(CH₂COOR¹¹)COOR¹², (CH₂)_(n)N(CH₂CONH₂)COOR¹¹, (CH₂)_(n)N(CH₂CONH₂)CONH₂, (CH₂)_(n)CHR¹³COR¹¹, (CH₂)_(n)CHR¹³COOR¹¹, (CH₂)_(n)CHR¹³CH₂OR¹⁴, (CH₂)_(n)OCN and (CH₂)_(n)NCO, R¹¹, R¹² are independently selected from H, A, (CH₂)_(m)Ar³ and (CH₂)_(m)Het, or, in NR¹¹R¹², R¹¹ and R¹² form, together with the N-Atom they are bound to, a 5-, 6- or 7-membered heterocycle which optionally contains 1 or 2 additional hetero atoms, selected from N, O an S, R¹³, R¹⁴ are independently selected from H, Hal, A, (CH₂)_(m)Ar⁴ and (CH₂)_(m)Het, A is selected from alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl alkoxy and alkoxyalkyl, Ar³, Ar⁴ are independently from one another aromatic hydrocarbon residues comprising 5 to 12 carbon atoms which are optionally substituted by one or more substituents, selected from A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶, COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵, SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵, Het is a saturated, unsaturated or aromatic heterocyclic residue which is optionally substituted by one or more substituents, selected from A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶, COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁶, NR⁶SO₂A, COR¹⁵, SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵, R¹⁵, R¹⁶ are independently selected from H, A, and (CH₂)_(m)Ar⁵, Ar⁵ is a 5- or 6-membered aromatic hydrocarbon which is optionally substituted by one or more substituents selected from methyl, ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN, OH, NH₂ and CF₃, n, m are independently of one another 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4 or 5, q is 0, 1, 2, 3 or 4, u is 0, 1, 2 or 3, Y is selected from O, S, NR²¹, C(R²²)—NO₂, C(R²²)—CN and C(CN)₂, R²¹ is H, Hal, A, (CH₂)_(m)Ar⁴ and (CH₂)_(m)Het R²² is H, A, (CH₂)_(m)Ar³ and (CH₂)_(m)Het, and the salts and solvates thereof.
 5. A method according to claim 1, wherein said compound is selected from


6. (canceled)
 7. (canceled)
 8. A method according to claim 1, wherein said kinases are raf-kinases.
 9. (canceled)
 10. (canceled)
 11. (canceled)
 12. (canceled)
 13. (canceled)
 14. (canceled)
 15. (canceled)
 16. A method according to claim 1, wherein said disorders are selected from hyperproliferative and nonhyperproliferative disorders.
 17. A method according to claim 1, wherein said disorder is cancer.
 18. A method according to claim 1, wherein said disorder is noncancerous.
 19. A method according to claim 1 wherein said noncancerous disorder is selected from infection, psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immunodeficiency diseases.
 20. A method according to claim 1, wherein said disorders are selected from brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer, renal cancer, colorectal cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynaecological cancer, thyroid cancer, lymphoma, chronic leukemia and acute leukemia.
 21. A method according to claim 1, wherein said disorders are selected from arthritis, restenosis, fibrotic disorders, mesangial cell proliferative disorders, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection, glomerulopathies, metabolic disorders, inflammation and neurodegenerative diseases.
 22. (canceled)
 23. A method according to claim 8, wherein said raf-kinase is selected from A-Raf, B-Raf and c-Raf-11.
 24. (canceled)
 25. (canceled)
 26. (canceled)
 27. A method according to claim 1, wherein said disorder is cancerous cell growth mediated by raf-kinase.
 28. (canceled)
 29. A compound of formula III,

wherein L¹ is Cl, Br, I, OH, a reactive esterified OH-group or a diazonium moiety, R⁸ is selected from H, A, cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)OR¹¹, (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COOR¹², (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)NR¹¹COR¹³, (CH₂)_(n)NR¹¹CONR¹¹R¹², (CH₂)_(n)NR¹¹SO₂A, (CH₂)_(n)SO₂NR¹¹R¹², (CH₂)_(n)S(O)_(n)R¹³, (CH₂)_(n)OC(O)R¹³, (CH₂)_(n)COR¹³, (CH₂)_(n)SR¹¹, CH═N—OA, CH₂CH═N—OA, (CH₂)_(n)NHOA, (CH₂)_(n)CH═N—R¹¹, (CH₂)_(n)OC(O)NR¹¹R¹², (CH₂)_(n)NR¹¹COOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂OR¹³, (CH₂)_(n)N(R¹¹)CH₂CH₂OCF₃, (CH₂)_(n)N(R¹¹)C(R¹³)HCOOR¹², C(R¹³)HCOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂N(R¹²)CH₂COOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂NR¹¹R¹², CH═CHCOOR¹¹, CH═CHCH₂NR¹¹R¹², CH═CHCH₂NR¹¹R¹², CH═CHCH₂OR¹³, (CH₂)_(n)N(COOR¹¹)COOR¹², (CH₂)_(n)N(CONH₂)COOR¹¹, (CH₂)_(n)N(CONH₂)CONH₂, (CH₂)_(n)N(CH₂COOR¹¹)COOR¹², (CH₂)_(n)N(CH₂CONH₂)COOR¹¹, (CH₂)_(n)N(CH₂CONH₂)CONH₂, (CH₂)_(n)CHR¹³COR¹¹, (CH₂)_(n)CHR¹³COOR¹¹, (CH₂)_(n)CHR¹³CH₂OR¹⁴, (CH₂)_(n)OCN and (CH₂)_(n)NCO, p is 0, 1, 2, 3, 4 or 5, Ar¹ is selected from aromatic hydrocarbons containing 6 to 14 carbon atoms and ethylenical unsaturated or aromatic heterocyclic residues containing 3 to 10 carbon atoms and one or two hetero atoms, independently selected from N, O and S, Y is selected from O, S, NR²¹, C(R²²)—NO₂, C(R²²)—CN and C(CN)₂, R¹¹, R¹² are independently selected from H, A, (CH₂)_(m)Ar³ and (CH₂)_(m)Het, or, in NR¹¹R¹², R¹¹ and R¹² form, together with the N-Atom they are bound to, a 5-, 6- or 7-membered heterocycle which optionally contains 1 or 2 additional hetero atoms, selected from N, O an S, n, m are independently of one another 0, 1, 2, 3, 4, or 5, A is selected from alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, alkoxy and alkoxyalkyl, R¹³, R¹⁴ are independently selected from H, Hal, A, (CH₂)_(m)Ar⁴ and (CH₂)_(m)Het, Ar³, Ar⁴ are independently from one another aromatic hydrocarbon residues comprising 5 to 12 carbon atoms which are optionally substituted by one or more substituents, selected from A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵, SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵, Het is a saturated, unsaturated or aromatic heterocyclic residue which is optionally substituted by one or more substituents, selected from A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶, COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵, SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵, R¹⁵, R¹⁶ are independently selected from H, A, and (CH₂)_(m)AR⁵, Ar⁵ is a 5- or 6-membered aromatic hydrocarbon which is optionally substituted by one or more substituents selected from methyl, ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN, OH, NH₂ and CF₃. u is 0, 1, 2 or 3, R²¹ is H, Hal, A, (CH₂)_(m)Ar⁴ and (CH₂)_(m)Het, R²² is H, A, (CH₂)_(m)Ar³ and (CH₂)_(m)Het.
 30. A compound of formula IV,

wherein L², L³ are independently from one another H or a metal ion, R⁹ and R¹⁰ are independent from one another selected from H, A, cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)OR¹¹, (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COOR¹², (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)NR¹¹COR¹³, (CH₂)_(n)NR¹¹CONR¹¹R¹², (CH₂)_(n)NR¹¹SO₂A, (CH₂)_(n)SO₂NR¹¹R¹², (CH₂)_(n)S(O)_(u)R¹³, (CH₂)_(n)OC(O)R¹³, (CH₂)_(n)COR¹³, (CH₂)_(n)SR¹¹, CH═N—OA, CH₂CH═N—OA, (CH₁)_(n)NHOA, (CH₂)_(n)CH═N—R¹¹, (CH₂)_(n)OC(O)NR¹¹R¹², (CH₂)_(n)NR¹¹COOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂OR¹³, (CH₂)_(n)N(R¹¹)CH₂CH₂OCF₃, (CH₂)_(n)N(R¹¹)C(R¹³)HCOOR¹², C(R¹³)HCOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂N(R¹²)CH₂COOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂NR¹¹R¹², CH═CHCOOR¹¹, CH═CHCH₂NR¹¹R¹², CH═CHCH₂NR¹¹R¹², CH═CHCH₂OR¹³, (CH₂)_(n)N(COOR¹¹)COOR¹², (CH₂)_(n)N(CONH₂)COOR¹¹, (CH₂)_(n)N(CONH₂)CONH₂, (CH₂)_(n)N(CH₂COOR¹¹)COOR¹², (CH₂)_(n)N(CH₂CONH₂)COOR¹¹, (CH₂)_(n)N(CH₂CONH₂)CONH₂, (CH₂)_(n)CHR¹³COR¹¹, (CH₂)_(n)CHR¹³COOR¹¹, (CH₂)_(n)CHR¹³CH₂OR¹⁴, (CH₂)_(n)OCN and (CH₂)_(n)NCO, A is selected from alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, alkoxy and alkoxyalkyl, R¹¹, R¹² are independently selected from H, A, (CH₂)_(m)Ar³ and (CH₂)_(m)Het, or, in NR¹¹R¹², R¹¹ and R¹² form, together with the N-Atom they are bound to, a 5-, 6- or 7-membered heterocycle which optionally contains 1 or 2 additional hetero atoms, selected from N, O an S, k, n, m are independently of one another 0, 1, 2, 3, 4, or 5, R¹³, R¹⁴ are independently selected from H, Hal, A, (CH₂)_(m)Ar⁴ and (CH₂)_(m)Het, Ar³, Ar⁴ are independently from one another aromatic hydrocarbon residues comprising 5 to 12 carbon atoms which are optionally substituted by one or more substituents, selected from A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶, COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵, SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵, q is 0, 1, 2, 3, or 4, X represents a bond or is (CR¹¹R¹²)_(h), or (CHR¹¹)_(h)-Q-(CHR¹²)_(i), Ar² is selected from aromatic hydrocarbons containing 6 to 14 carbon atoms and ethylenical unsaturated or aromatic heterocyclic residues containing 3 to 10 carbon atoms and one or two hetero atoms, independently selected from N, O and S, Het is a saturated, unsaturated or aromatic heterocyclic residue which is optionally substituted by one or more substituents, selected from A, Hal, NO₂—CN, OR¹⁵, NR¹⁵R¹⁶, COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵, SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵, R¹⁵, R¹⁶ are independently selected from H, A, and (CH₂)_(m)Ar⁵, Ar⁵ is a 5- or 6-membered aromatic hydrocarbon which is optionally substituted by one or more substituents selected from methyl, ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN, OH, NH₂ and CF₃, u is 0, 1, 2 or 3, h, i are independently from each other 0, 1, 2, 3, 4, 5 or 6, and r is 0, 1, 2, 3, 4 or
 5. 31. A method according to claim 3, wherein Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl, p is 1, 2 or 3, R⁸ is selected from the group consisting of alkyl comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹¹, (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³ wherein n is 0 or 1, u is 0 or 2, q is 0 or 1, and X is O, S, NR¹⁵, CHOR¹¹, CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, or CH₂CH₂O.
 32. A method according to claim 31, wherein A² is phenyl or pyridinyl.
 33. A method according to claim 31, wherein X is O or S.
 34. A method according to claim 31, wherein Y is O or S.
 35. A method according to claim 31, wherein A¹ is phenyl or oxazolyl.
 36. A method according to claim 31, wherein A² is pyridinyl.
 37. A method according to claim 31, wherein X is O.
 38. A method according to claim 31, wherein Y is O.
 39. A method according to claim 31, wherein Ar¹ is phenyl, pyridinyl or isoxazolyl.
 40. A method according to claim 39, wherein A¹ is phenyl.
 41. A method according to claim 3, wherein A is alkyl having 1 to 10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having 3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, or C_(u)H_(2u+1)—O—(CH₂)_(v) wherein u is 1 to 6 and v is 1 to
 6. 42. A method according to claim 4, wherein A is alkyl having 1 to 10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having 3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, or C_(u)H_(2u+1)—O—(CH₂)_(v) wherein u is 1 to 6 and v is 1 to
 6. 43. A method according to claim 39, wherein A is alkyl having 1 to 10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having 3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, or C_(u)H_(2u+1)—O—(CH₂)_(v) wherein u is 1 to 6 and v is 1 to
 6. 44. A compound according to claim 35, wherein A is alkyl having 1 to 10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having 3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, or C_(u)H_(2u+1)—O—(CH₂)_(v) wherein u is 1 to 6 and v is 1 to
 6. 45. A compound according to claim 40, wherein A is alkyl having 1 to 10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having 3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, or C_(u)H_(2u+1)—O—(CH₂)_(v) wherein u is 1 to 6 and v is 1 to
 6. 46. A compound according to claim 39, wherein A² is pyridinyl and X is O.
 47. A compound according to claim 35, wherein A² is pyridinyl and X is O.
 48. A compound according to claim 40, wherein A² is pyridinyl and X is O.
 49. A compound according to claim 43, wherein A² is pyridinyl and X is O.
 50. A compound according to claim 44, wherein A² is pyridinyl and X is O.
 51. A compound according to claim 45, wherein A² is pyridinyl and X is O. 